Parkinsonism genes: culprits and clues


  • Asa Abeliovich,

    1. Departments of Pathology and Neurology, Center for Neurobiology and Behavior, and Taub Institute, Columbia University, College of Physicians and Surgeons 15–403, 630 W 168th. St., New York, NY 10032 USA
    Search for more papers by this author
  • M. Flint Beal

    1. Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York, NY, USA
    Search for more papers by this author

Address correspondence and reprint requests to Asa Abeliovich, Departments of Pathology and Neurology, Center for Neurobiology and Behavior, and Taub Institute, Columbia University, College of Physicians and Surgeons 15–403, 630 W 168th. St., New York, NY 10032 USA. Email:


Parkinson's disease (PD) is characterized by a unique clinical constellation that includes: slowness, rigidity, gait difficulty, and tremor at rest. Pathological studies have linked this presentation to the loss of midbrain dopamine neurons (Gelb et al. 1999) although other neuronal populations are also targeted in PD. Epidemiological data implicate both genetic and environmental factors in the etiology of the disease. The identification of a series of genes that underlie relatively rare, familial forms of Parkinsonism (a clinical term that encompasses ‘sporadic’ PD, familial Parkinson's-like forms, as well as other related syndromes) has brought excitement to the field. Three of the mutated familial Parkinsonism (FP) genes: Parkin, DJ-1, and PINK1, typically present with apparent autosomal recessive inheritance and are implicated in mitochondria and oxidative stress-related survival pathways. Two other FP genes: α-Synuclein (αSyn) and LRRK2, present in an autosomal dominant pattern and are associated with prominent intracellular protein inclusions. A series of recent publications suggest novel pathways that may link the FP genes.

Abbreviations used

familial Parkinsonism


Jun kinase


Lewy body


Parkinson's disease


phosphotidyl inositol kinase-3


RNA inhibition

The recessive FP genes

Each of the autosomal recessive familial Parkinsonism (FP) genes is broadly expressed in many cell types and organs, suggesting that these genes do not serve strictly neuron-specific functions. This is unexpected given the relatively targeted neuronal pathology in FP or Parkinson's disease (PD), and leaves open the question of what underlies the apparent cell type specificity of the disease. A favored hypothesis has been that mutations in the FP genes may sensitize cells to intrinsic or extrinsic toxic insults that are particularly prominent for midbrain dopamine neurons (Betarbet et al. 2002; Xu et al. 2002). Consistent with this, pathological examination of PD patient brains has implicated oxidative stress and mitochondrial dysfunction (Beal 2003). Furthermore, a very rare Parkinsonism syndrome has been associated with the dopamine neuron-specific toxin (1-methyl 4-phenyl 1,2,3,6-tetrahydropyridine) MPTP, which leads to oxidative stress and mitochondrial dysfunction (Langston et al. 1984). Also, systemic administration of rotenone, a mitochondrial complex I inhibitor, induces dopamine neuron loss in rodents (Betarbet et al. 2000). Further insights into the function of the FP genes will likely also shed light on the role of environmental factors in PD.


The first identified recessive FP gene, parkin, encodes a protein with two Really Interesting New Gene (RING) domains at the carboxy terminus and a ubiquitin-like domain at the amino terminus (Kitada et al. 1998). Based on the domain structure of parkin, several groups hypothesized and went on to demonstrate an association with ubiquitin ligase activity (Imai et al. 2000; Shimura et al. 2000; Zhang et al. 2000). Mammalian genomes encode a large family (over 600) of RING domain proteins and a number of these function as ubiquitin ligases, which are enzymes that play gatekeeper roles in the addition of ubiquitin onto distinct sets of substrates. Target proteins that are covalently tagged with single or multiple ubiquitin polypeptide moieties are typically destined for degradation by the proteasomal complex, although other ubiquitin-mediated fates have also been well described (Hershko and Ciechanover 1998). RING finger ubiquitin ligases are often composed of multiple protein subunits, including Cullin and F-box protein family members, and there is evidence that parkin functions within such a complex (Staropoli et al. 2003). Parkin may also associate with the protein chaperones Hsp70 and CHIP (Imai et al. 2002).

A simplistic model for the action of parkin mutations is that these lead to a wholesale derangement of the cellular protein degradation machinery (a cellular ‘garbage strike’) but the diversity of mammalian ubiquitin ligases argues against this. A more widely held view is that parkin degrades a unique subset of target proteins, perhaps PD associated proteins such as αSynuclein (αSyn), that accumulate in neurons. However, direct evidence that αSyn or other PD-associated proteins are major substrates of parkin remains unconfirmed. Central nervous system neurons in patients that lack parkin tend not to display the large protein aggregates that typify sporadic disease (Mizuno et al. 1999), termed Lewy bodies, which are composed in part of αSyn (Spillantini et al. 1997). Furthermore, parkin deficiency does not appear to alter inclusion body formation or neurodegeneration in the context of mutant αSyn over-expression in a mouse model of α-Synucleinopathy (von Coelln et al. 2006). A series of additional putative parkin substrates have been identified, primarily through protein interaction assays, including synphilin-1 (Chung et al. 2001), endothelin-like receptor-1 (Imai et al. 2001), synaptotagmin IX (Huynh et al. 2003), Cyclin E (Staropoli et al. 2003), aminoacyl-tRNA synthetase cofactor p38 (Ko et al. 2005), and far upstream binding protein 1 (Ko et al. 2006). Of these, the latter two are further supported as relevant parkin substrates by their apparently increased accumulation in parkin deficient mouse brain. However, the parkin critical substrates in FP remain to be determined.

A third hypothesis is that parkin functions within a specific signaling pathway that is required for survival in neurons. Consistent with this, parkin over-expression is protective in several cellular models of apoptosis (Petrucelli et al. 2002; Darios et al. 2003; Staropoli et al. 2003), and a number of the putative parkin substrates above may function within survival pathways. A hurdle to the detailed analysis of parkin in mammalian neuronal survival has been that knockout mice deficient in parkin display little or no alteration in dopamine neuron survival (Goldberg et al. 2003; Itier et al. 2003; Perez and Palmiter 2005), although one study found evidence for a small but significant reduction in the number of norepinephrine neurons in the locus coeruleus (Von Coelln et al. 2004). There is some evidence for altered dopamine neuron-related behaviors as well as altered startle response in parkin-deficient mice, but it remains possible that these phenotypes may relate to the genetic background of the mutant mice and not to parkin loss (see Perez and Palmiter 2005).

Analysis of Drosophila mutants that are deficient in an orthologue of parkin reveal striking mitochondrial pathology (Greene et al. 2003), which is unexpected given the relatively subtle phenotype of parkin deficiency in rodents. The Drosophila phenotype is most prevalent in flight muscle and sperm, two highly metabolic tissues, and progresses with age, culminating in an inability to fly, male sterility, and reduced survival. Neuronal pathology, and dopamine neurons in particular, appear variable (Greene et al. 2003; Pesah et al. 2004). Consistent with a mitochondrial defect in the parkin mutant Drosophila leading to oxidative stress and toxicity, over-expression of glutathione s-transferase, an antioxidant, suppresses neurodegeneration in Drosophila parkin mutants (Whitworth et al. 2005). Additional analyses have indicated that parkin over-expression can protect mammalian tissue culture cell lines from mitochondrial toxins (Darios et al. 2003), and mice deficient in parkin display subtle abnormalities in mitochondrial parameters (Palacino et al. 2004). Mammalian parkin is primarily localized to the cytoplasm of postmitotic cells, but a fraction appears to associate with the outer mitochondrial membrane (Darios et al. 2003). Furthermore, in proliferating tumor cell lines, parkin may preferentially localize to mitochondria and enhance mitochondrial biogenesis through an association with mitochondria transcription factor A (Kuroda et al. 2006), although the antibodies used in this study have not been rigorously validated in terms of their specificity.

A potential link between parkin, an FP gene, and mitochondria is tempting because of the prior association of Parkinsonism with mitochondrial dysfunction (Beal 2003), but the muscle and sperm tissue involvement observed in Drosophila is unexpected, given the neuron specificity of the mammalian phenotype. It is possible that parkin plays a conserved protective role related to mitochondria in both Drosophila and mammals, but that Drosophila tissues are subject to very different stressors from their mammalian counterparts. An alternative but less likely interpretation is that Drosophila parkin may not represent a true functional orthologue of the mammalian gene. The human parkin gene has not been demonstrated to complement loss of the Drosophila gene; thus, although the genes display a high degree of sequence similarity (59%) they may not be functionally interchangable. Finally, it is interesting to speculate as to how Parkin may protect from mitochondrial stress. Mammalian parkin is primarily cytoplasmic in postmitotic neurons, thus raising the possibility that parkin might function within a cytoplasmic signaling cascade; alternatively, a pool of mammalian Parkin may play a role directly within mitochondria (Darios et al. 2003; Kuroda et al. 2006).


A more direct link between autosomal recessive FP and mitochondria came with the identification of FP mutations in PINK1, which harbors a mitochondrial targeting motif as well as a serine/threonine kinase domain (Valente et al. 2004). Further analysis has revealed that PINK1 protein appears to accumulate within the intermembrane space of mitochondria (Silvestri et al. 2005). PINK1 mutations that are associated with FP are scattered through the gene; some appear to reduce the accumulation of the protein, whereas others likely impair kinase activity, consistent with a loss-of-function mechanism.

Strikingly, Drosophila deficient in PINK1 phenocopy essentially all of the characteristics of parkin null Drosophila. Two recent studies that investigate Drosophila homozygous for PINK1 null alleles (Clark et al. 2006; Park et al. 2006), and a third study that uses RNAi to knock down expression of PINK1 (Yang et al. 2006), all show that PINK1 loss leads to a profound defect in inflight muscles characterized by a progressive mitochondrial myopathy, with immensely swollen mitochondria and the inability to fly. The muscle defect is not prominent in other, less metabolically active Drosophila muscle groups, as with parkin mutants, suggesting a role for metabolic activity in the degeneration. Furthermore, PINK1 deficient Drosophila display defective sperm and reduced longevity, consistent with the parkin null phenotype. Also reminiscent of the parkin phenotype, dopamine neuron number appears variable in PINK1 Drosophila in these studies. The PINK1 deficit leads to ATP depletion and apoptosis and can be largely suppressed by over-expression of a Drosophila orthologue of Bcl-2, an antiapoptotic protein that is protective for mitochondrial integrity and function.

The PINK1 null phenotype can be largely suppressed by Drosophila parkin over-expression, but not vice versa (Clark et al. 2006; Park et al. 2006). These data represent the first direct evidence of a genetic interaction between the recessive FP genes.

The protective effects of parkin over-expression in PINK1-deficient Drosophila appear specific, as parkin over-expression failed to protect from other toxic insults in the Drosophila model. These data strongly suggest a genetic pathway, with parkin functioning downstream of PINK1. It appears that human parkin can also rescue the function of PINK1 loss in Drosophila, which strengthens the argument that the pathway is conserved (Clark et al. 2006; Park et al. 2006).


A third FP gene, DJ-1, has been associated with autosomal recessive Parkinsonism (Bonifati et al. 2003). DJ-1 had previously been isolated in a proteomic screen for cytoplasmic proteins that are structurally modified with respect to isoelectric point upon exposure to paraquat, a toxin that leads to the generation of reactive oxygen species and has been associated with dopamine neuron toxicity (Mitsumoto et al. 2001). Consistent with this, DJ-1 deficiency sensitizes dopamine neurons to oxidative stressors in vitro (Shendelman et al. 2004) and in the intact CNS (Kim et al. 2005a). Furthermore, DJ-1 over-expression appears protective against a number of oxidative toxic insults (Canet-Aviles et al. 2004; Martinat et al. 2004; Taira et al. 2004). DJ-1 encodes a small protein within the highly conserved ThiJ domain family (named after the e. Coli YajL/ThiJ protein of unknown function, Wilson et al. 2005), which is associated with chaperone, protease, and other activities. DJ-1 displays chaperone activity that is activated by oxidative stress and inactive in a reducing environment (Shendelman et al. 2004; Zhou et al. 2006), consistent with the structural modification of the protein. The redox regulation of DJ-1 chaperone activity is unique among characterized mammalian chaperone proteins. Oxidized DJ-1 appears broadly active as a chaperone towards a variety of protein substrates, including αSynuclein, and DJ- inhibits fibrillization of αSynuclein in vitro and in vivo (Shendelman et al. 2004; Zhou et al. 2006). It remains possible that DJ-1 may harbor other enzymatic functions, such as protease (Olzmann et al. 2004) and antioxidant activities (Taira et al. 2004). DJ-1 also may function within a post-transcriptional RNA-binding complex (Hod et al. 1999) or a transcriptional DNA-binding regulatory complex (Takahashi et al. 2001; Xu et al. 2005), potentially regulating cellular protective mechanisms such as glutathione biosynthesis (Zhou and Freed 2005).

Mice deficient in DJ-1, similar to Parkin and PINK1 mice, display a normal complement of dopamine neurons and subtle alterations in dopamine neuron function (Goldberg et al. 2005; Kim et al. 2005a). There are two Drosophila orthologues of DJ-1: DJ-1a, which is expressed ubiquitously, and DJ-1b, most highly expressed in the testes and at lower levels elsewhere. Loss of DJ-1b leads to increased sensitivity to oxidative stressors in the form of hydrogen peroxide (Menzies et al. 2005; Meulener et al. 2005a), although paraquat sensitivity was variable between the reports. Lifespan and dopamine neuron number appeared unaltered in DJ-1b Drosophila. Interestingly, DJ-1a mutations were identified in a Drosophila genetic screen for mutations that sensitize photoreceptor cells to Phosphatase and Tensin homologue (PTEN) over-expression (Park et al. 2005), suggesting that DJ-1 may function within the Kinase (PTEN/AKT) survival signaling pathway.

A recessive FP pathway

It is tempting to speculate on a direct protein interaction between PINK1 and parkin based on the genetic studies in Drosophila. Several studies have suggested the existence of complexes that include multiple FP-associated proteins (Shimura et al. 2001; Shendelman et al. 2004; Meulener et al. 2005b; Tang et al. 2006; Yang et al. 2006), but the functional significance and specificity of such complexes has not been established. Co-immunoprecipitation of over-expressed, epitope-tagged PINK1 and parkin proteins has been reported (Yang et al. 2006), but it remains unclear if such a complex functions in vivo. Furthermore, these proteins may primarily reside in separate cellular compartments, as PINK1 accumulates in mitochondria and parkin mostly accumulates in the cytoplasm within postmitotic neurons, although a proportion of mammalian parkin protein may associate with the mitochondria outer membrane (Darios et al. 2003). The two proteins may associate in the cytoplasm prior to the transport of PINK1 to the mitochondria. Alternatively, parkin and PINK1 may not physically interact but rather functionally modify one another: for instance, the activation of PINK1 kinase may be required for parkin ubiquitin ligase activity.

A third mechanism, which may be most likely, is that these proteins share common substrates (Fig. 1). A number of RING domain ubiquitin ligases target phosphorylated substrates; this is a particularly prominent regulatory mechanism in the context of ubiquitination in cell cycle regulation (Willems et al. 1999). It is tempting to speculate on the nature of putative PINK1 and parkin substrates: candidates would include mitochondrial proteins that are released to the cytoplasm in the context of cellular stress, or other apoptosis-related proteins.

Figure 1.

 A hypothetical molecular model for a recessive Parkinsonism signaling pathway. Substrate proteins (X) that remain to be identified are activated by oxidative stress or other factors and accumulate in a toxic state (Tox-X). Modifications, including phosphorylation by PINK1 and ubiquitination by Parkin, serve to inhibit Tox-X. DJ-1 may function to inhibit the accumulation of Tox-X upstream of PINK1 and Parkin. As PINK1 is primarily localized to mitochondria, whereas Parkin and DJ-1 are enriched in the cytoplasm, it is possible that processing of Tox-X requires translocation. Alternatively, DJ-1, Parkin, and PINK1 have all been associated with mitochondria, and furthermore it is possible that the three may co-assemble into a multiprotein complex. PINK1 may modify Parkin activity within such a complex, either directly or indirectly. Tox-X is predicted to induce Jnk activation, subsequent expression of pro-apoptotic Bcl-2 family members such as Bax, and ultimately cell death.

A role for DJ-1 in a recessive FP pathway is less clear. Interestingly, DJ-1 over-expression does not appear to rescue PINK1 mutant Drosophila (Clark et al. 2006; Park et al. 2006), suggesting that DJ-1 may either function upstream of this signal or in another pathway. It is unknown whether the Drosophila parkin null phenotype is mitigated by DJ-1 over-expression, or vice versa. Furthermore, Drosophila that harbor mutations in both of these genes have not been described. Analysis of FP patients has identified a family with apparent digenic inheritence of heterozygous mutations in PINK1 and DJ-1, consistent with the notion that these two genes are components of a common pathway (Tang et al. 2006). Consistent with this, co-immunoprecipitation studies in tissue culture cells that over-express PINK1 and DJ-1 suggest that these proteins may physically interact (Tang et al. 2006). There is evidence that parkin and DJ-1 may associate in a multiprotein complex under conditions of oxidative stress or in the context of FP-associated DJ-1 mutations (Moore et al. 2005), consistent with the role of protein chaperones in delivering substrates to the ubiquitin protein degradation machinery. Of note, DJ-1 is primarily cytoplasmic but has also been reported to accumulate in mitochondria (Zhang et al. 2005), particularly in the context of oxidative stress (Canet-Aviles et al. 2004).

Some clues have emerged as to the identity of signals that function downstream of the FP genes. Several studies have linked the recessive Parkinson's disease genes with common survival signaling components, including the pro- and antiapoptotic Bcl-2 family members (Clark et al. 2006; Park et al. 2006), c-Jun terminal kinase (Jnk) pathway activation (Jiang et al. 2004; Cha et al. 2005), and PTEN signaling pathway components (Kim et al. 2005b). The broad protective properties conferred by parkin over-expression in mammalian cells are consistent with the induction of common survival signals. In Drosophila, the parkin null phenotype can be mitigated by inactivation of the Jun kinase (Jnk) pathway (Cha et al. 2005), a pro-apoptotic signaling cascade in neurons. In the context of FP deletion, Jnk activation is predicted to induce expression of Bax and other pro-apoptotic members of the Bcl-2 protein family through both transcriptional and post-transcriptional mechanisms. Consistent with this model, over-expression of the Drosophila Bcl-2 homologue, Buffy (an antiapoptotic protein that promotes the integrity of mitochondrial membranes) protects PINK-1 mutant Drosophila (Clark et al. 2006; Park et al. 2006).

Another survival signaling cascade implicated downstream of the recessive FP genes is the phosphotidyl inositol kinase-3 (PI3K) pathway. PI3K is induced by a number of extracellular signals, including neurotrophins and glial-derived neurotrophic factor, leading to accumulation of the lipid PI(3,4,5)P3, up-regulation of AKT kinase activity, and ultimately, inhibition of pro-apoptotic signals (Datta et al. 1999). Yang et al. (Yang et al. 2005) investigated the function of Drosophila DJ-1a using an RNA inhibition (RNAi)-based transgenic model, and observed a neurodegenerative phenotype both in photoreceptors and in dopamine neurons. The neurodegenerative phenotype could be suppressed by over-expression of either AKT or of PI3K catalytic subunit. In contrast over-expression of a dominant negative catalytic subunit of PI3K, or of wild type PTEN, a lipid phosphatase and tumor suppressor that antagonizes PI3K activity, enhanced the neurodegenerative phenotype of DJ-1 RNAi. Interestingly, RNAi-mediated suppression of either DJ-1a or Parkin in Drosophila appears to suppress activation of AKT, suggesting that AKT activation may be a common mechanism for the recessive Parkinsonism genes. A caveat here is that the Yang et al. (2006) study describe an unexpectedly severe phenotype in the RNAi DJ-1a Drosophila, given that the DJ-1a null Drosophila harbor a normal complement of dopamine neurons and have not been reported to undergo photoreceptor degeneration. Thus, it remains possible that ‘off-target’ effects of the RNAi construct on genes other than DJ-1a underlie the phenotype. However, an independent genetic screen for p-element insertion mutations that enhance the phenotype of PTEN-induced neurodegeneration in Drosophila photoreceptors identified DJ-1a (Kim et al. 2005b), reinforcing a role for DJ-1 in this pathway. Finally, PINK1 was originally identified in a screen for genes that are transcriptionally induced by PTEN over-expression (Unoki and Nakamura 2001), linking another FP gene with this pathway.

The Dominant FP Genes


αSyn mutations were initially identified in very rare families that harbor autosomal dominant FP (Polymeropoulos 2000). Subsequently, the encoded protein was found to be a major component of Lewy body (LB) intra-cytoplasmic neuronal aggregates that typify ‘sporadic’ PD (Spillantini et al. 1997), lending credence to the notion that FP genes are relevant to the mechanism of sporadic PD. More recently, it has emerged that over-expression of wild type αSyn due to gene amplification of the locus is sufficient to cause an FP phenotype, although patients that harbor such mutations often display prominent extra-nigral pathology, typical of Lewy Body dementia (Singleton et al. 2003; Miller et al. 2004). In a number of model systems, including rodents (Giasson et al. 2002; Lee et al. 2002), Drosophila (Feany and Bender 2000) and yeast (Outeiro and Lindquist 2003), αSyn over-expression leads to cellular toxicity. There is evidence that this is due in part to the formation of toxic protein aggregates that are readily observed in vitro (Hashimoto et al. 1998; Conway et al. 2000; Rochet et al. 2000) and in vivo (Giasson et al. 2002; Lee et al. 2002). In addition, smaller protofibrillar aggregates, composed of 12–66 monomers (Lashuel et al. 2002) are precursors to large fibrillar amyloid inclusions and appear toxic in cell model systems. αSyn interacts with vesicular membranes in vivo and in vitro, leading to a structural transition in the protein to a more ordered state with increased secondary structure (Weinreb et al. 1996). Within neurons, αSyn appears to associate with synaptic vesicles in an activity dependent manner (Fortin et al. 2005) and plays a regulatory role in vesicular release of neurotransmitter (Abeliovich et al. 2000; Cabin et al. 2002; Fortin et al. 2005). Unexpectedly, αSyn over-expression can protect from neuronal process loss in the context of mutations in cysteine string protein, a synaptic vesicle associated protein, in mice (Chandra et al. 2005), but it is unclear how this relates to the pathological or normal functions of αSyn.

Transgenic mice that over-express FP-associated mutant αSyn in the CNS display evidence of dysfunction (Gispert et al. 2003) and neurodegeneration (Giasson et al. 2002; Lee et al. 2002). In some cases dopamine neuron toxicity is apparent (Kahle et al. 2001). Early pathological findings in αSyn mutant transgenic mice include loss of dopaminergic processes and synapses (Masliah et al. 2000). αSyn deficiency in knockout mice or in cell cultures in vitro leads to alterations in synaptic vesicle trafficking (Abeliovich et al. 2000; Cabin et al. 2002), consistent with a physiological role at axon terminals. Consistent with this, αSyn aggregates in PD are associated with axon pathology (Galvin et al. 1999). These data suggest the possibility that the pathological function of αSyn may relate to a physiological role of this protein at synapses.

Additional sites of action have been proposed for αSyn. In a recent analysis of spinal motor neurons undergoing degeneration in αSyn FP-associated A53T over-expressing transgenic mice, the mutant protein was found to be localized to the outer mitochondrial membrane (Martin et al. 2006). αSyn accumulation has also been associated with defective protein degradation due to proteasome dysfunction (Stefanis et al. 2001; Tanaka et al. 2001), altered macroautophagy (Stefanis et al. 2001), or defective chaperone-mediated autophagy (Cuervo et al. 2004). The latter two mechanisms shuttle a subset of cytoplasmic and organelle-associated proteins into the lysosomal degradation pathway. Most recently, studies of αSyn overexpression in Saccharomyces cerevisiase, Drosophila melanogaster, and Caenorhabditis elegans, suggest that αSyn accumulation specifically inhibits endoplasmic reticulum to golgi vesicular traffic (Cooper et al. 2006).


Most recently, FP autosomal dominant gene mutations were identified in LRRK2, a large gene that encompasses MLK-like kinase, Rho-like GTPase, WD40 repeat-domain, and leucine rich repeat domains (Paisan-Ruiz et al. 2004; Zimprich et al. 2004). LRRK2 autosomal dominant mutations appear to be relatively common genetic determinants of PD susceptibility. A single mis-sense allele of LRRK2, G2019S, may be associated with 1–2% of apparently ‘sporadic’ PD cases (Di Fonzo et al. 2005; Gilks et al. 2005; Nichols et al. 2005), and, remarkably, with over 10% of PD cases in specific populations such as Ashkenazi Jews and North African Arabs (Lesage et al. 2006; Ozelius et al. 2006). No single genetic mutation has previously been associated with a significant proportion of PD cases. Pathological examination of patients with LRRK2 mutations has revealed dopamine neuron degeneration in the substantia nigra of the ventral mid-brain, as expected, but also remarkable heterogeneity regarding other pathological features: some cases harbor αSyn-positive LB intracytoplasmic aggregates typical of sporadic PD, whereas other cases either lack LB aggregates, display widespread LB pathology in the cerebral cortex, or harbor Tau-positive axonal spheroids (Wszolek et al. 2004).

LRRK2 is a member of a family of proteins, termed ROCO-domain proteins, defined by a unique domain (Roc, for Ras of complex proteins) between the GTPase and kinase domains of family members (Bosgraaf and Van Haastert 2003). Interestingly, prior studies in Dictyostelium discoidum reveal that a LRRK2 orthologue termed Pats1 is required for normal cytokinesis, implicating LRRK2 in cytoskeletal regulation (Abysalh et al. 2003). LRRK2 appears to be broadly expressed throughout the CNS and elsewhere (Paisan-Ruiz et al. 2004; Zimprich et al. 2004), consistent with a basic cellular function. Unexpectedly, transcript levels may be relatively low in dopamine neurons and relatively high in the striatum (Galter et al. 2006; Melrose et al. 2006), although localization of LRRK2 protein by immunohistochemistry has not been reported. Mutations in LRRK2 appear to fall throughout all of the identified structural segments. Interestingly, the common G2019S mutation is predicted to alter a highly conserved region of the kinase domain termed the ‘activation loop’, based on structural homology to other protein kinases (Davies et al. 2002), and mutations within this segment may lead to altered kinase activity in vitro (West et al. 2005; Gloeckner et al. 2006). Kinase activity appears to be required for the toxicity of G2019S LRRK2 in tissue culture cell lines (Greggio et al. 2006).

The cellular and molecular basis of LRRK2 activity remain to be described. A possible mechanism of LRRK2 action is at the mitochondria, given the clear role of the autosomal recessive genes at this locus. There is evidence that a fraction of cellular LRRK2 protein may be present at mitochondrial membranes (West et al. 2005). Alternatively, the role of the LRRK2 homologue Pats1 in cytokinesis implicates this gene family in cytoskeletal process regulation. Also, the prominent Tau pathology is consistent with cytoskeletal dysfunction. Cytoskeletal abnormalities have long been implicated in sporadic PD (Trojanowski et al. 1993). Mutations in Tau (Goedert et al. 1998) and αSyn (Giasson et al. 2002) have been associated with abnormal axonal cytoskeletal dysfunction. Furthermore, dopaminergic axonal terminal damage is an early phenotypic marker of PD and precedes cell loss (Galvin et al. 1999; Willesen et al. 2002). It will be of interest to investigate whether LRRK2 mutations lead to similar alterations in animal models. Finally, there is evidence for LRRK2 association with intracellular membranes structures, such as golgi, endoplasmic reticulum, and mitochondria, based on cell fractionation and immunohistochemical studies of over-expressed, epitope-tagged LRRK2 protein in cultured cells (Gloeckner et al. 2006). A number of Rho-like GTPase proteins play regulatory roles in vesicular trafficking, and thus it is tempting to hypothesize such a function for LRRK2. However, the membrane association needs to be confirmed for native LRRK2 protein.


Autosomal dominant mutations in the microtubule-associated protein Tau are not associated with FP, but rather with a set of neurodegenerative syndromes including frontotemporal dementia with Parkinsonism (Yoshiyama et al. 2001), progressive supranuclear palsy, and corticobasal ganglionic degeneration. These syndromes present with broad neuronal loss, diverse cognitive and behavioral manifestations and pathological Tau inclusions that are associated with axonal defects (Lee et al. 2001). However, dopamine neuron loss is apparent in the context of Tau mutations in these syndromes. Furthermore, genetic association studies have linked certain alleles of Tau with an increased likelihood of PD, indicating that Tau may be a risk factor for PD (Martin et al. 2001). FP-associated LRRK2 mutations can present with Tau or αSyn pathology (Zimprich et al. 2004). These data blur the previously held view that Tau-associated neurodegeneration is distinct from αSyn-associated degeneration. Consistent with this, there is molecular evidence from in vitro aggregation studies that further suggest that Tau and αSyn aggregation can promote one another (Giasson et al. 2003).

A dominant FP pathway?

Several common themes have emerged from the analysis of the dominant FP-associated genes, although these cannot yet be placed simply into a molecular pathway. Clinical pathology indicates that mutations in LRRK2 can lead to both Tau and αSyn aggregation and pathology, suggesting that LRRK2 functions upstream of Tau and αSyn within a cascade (Singleton 2005) (Fig. 2). Both Tau and αSyn are normally localized to axonal processes in mature CNS neurons, whereas these proteins are sequestered to aggregates within axonal processes and soma in the context of mutations in the autosomal dominant FP genes. Aggregates of αSyn, Tau, or both, are likely pathogenic, although the mechanism of this toxicity remains unclear. Such aggregates may ultimately lead to oxidative stress and mitochondrial dysfunction; conversely, there is also evidence that oxidative stress may induce aggregation (Norris and Giasson 2005). With respect to αSyn, aggregation may be catalyzed by interactions with oxidized cholesterol or phospholipids (Bosco et al. 2006). As both αSyn and Tau proteins are normally present within axonal processes, it is predictable that mutations in these genes initially lead to axonal process dysfunction.

Figure 2.

 A hypothetical model for a dominant Parkinsonism signaling pathway. As LRRK2 mutations lead to both αSyn and Tau inclusions, LRRK2 is likely to function upstream in this pathway. Mutations in the two FP-associated genes as well as in Tau have been associated with a variety of cellular insults, including cytoskeletal dysfunction, protein aggregation, aberrant vesicular trafficking, and mitochondrial dysfunction. The primary cellular lesion in the context of neurodegeneration is unclear.


The identification of a series of genes associated with FP has injected great excitement to the PD field. Insights from Drosophila mutants have served to link the autosomal recessive FP genes into a genetic pathway that leads to mitochondrial dysfuction and oxidative stress. Mutations in a recently identified autosomal dominant FP gene, LRRK2, lead to a broad spectrum of clinical and pathological presentations, blurring the lines between previously distinct neurodegenerative syndromes. A central question that remains is how the dominant and recessive FP genes relate to one another? Segregation of the FP gene syndromes into dominant and recessive subsets is a useful construct to further explore the mechanisms underlying neurodegeneration in FP. It is likely that similar mechanisms are at play in the common sporadic disease. The basis for the relative predilection of pathological changes in FP and PD to mid-brain dopamine neurons remains to be elucidated, but may relate directly to the presence of dopamine and its metabolites within processes, leading to oxidative stress and mitochondrial dysfunction (Betarbet et al. 2002; Beal 2003).