Alpha-synuclein, LRRK2 and Parkinson's Disease
Alpha-synuclein, LRRK2 and Parkinson's Disease
Dominantly inherited mutations in the LRRK2 gene are perhaps the most common cause of familial and sporadic PD, which have been identified in approximately 3–5% of familial and 1–3% of sporadic PD cases, although the frequency may vary greatly in different populations. The LRRK2 gene encodes a rather large protein of 2527 amino acids compared with α-syn. LRRK2 contains 12 leucine-rich repeats (LRRs) in the N-terminus, a Roc domain and a MAPKKK domain in the middle, and a WD40 domain in the C-terminus. The putative kinase and GTPase activities of LRRK2 might be important in the pathogenesis of PD. In vitro studies indicate that several PD-specific mutations increase LRRK2 autophosphorylation and phosphorylation of generic protein kinase substrates. For example, the G2019S mutation at the kinase domain of LRRK2 increases its autophosphorylation by twofold. Meanwhile, a reciprocal regulation of its GTPase and kinase activities seems to influence the function and cytotoxicity of LRRK2. While LRRK2 is mainly a cytoplasmic protein, it is also partially associated with membrane organelles such as mitochondria, ER, Golgi apparatus, endosomes and synaptic vesicles. This characteristic distribution of LRRK2 may indicate an involvement of LRRK2 in membrane trafficking as suggested by findings in transgenic mouse models.
A variety of transgenic mice have been generated to study the function of LRRK2. However, none of these LRRK2 transgenic mice have developed PD-like neuropathology, such as formation of LB-like α-syn-positive inclusions and loss of SNc DA neurons. In addition, none of the LRRK2 knockout mice displayed obvious motor, behavioral or neuropathological phenotypes. By contrast, LRRK2 knockout, as well as G2019S and kinase-dead knock-in mice, developed profound pathological lesions in the periphery tissues, such as the kidney and lung of aged animals, suggesting that LRRK2 is more critically involved in maintaining the normal functions of cells in the kidney and lung, which happen to process robust secretory pathways. A further investigation of LRRK2's exact role in protein secretion and degradation in kidney and lung cells may provide significant molecular insights into the pathophysiological functions of LRRK2 in neurons and PD. Taken collectively, these observations from LRRK2 knockout and transgenic mice suggest that LRRK2 might play a rather subtle or selective role in modulating the physiological function and survival of neurons. For example, studies from primary cultured neurons derived from LRRK2 transgenic and knockout mice demonstrate an involvement of LRRK2 in axon and dendrite outgrowth during neuronal development, likely through regulating the dynamics of actin assembly or ER/Golgi vesicle trafficking.
LRRK2
Dominantly inherited mutations in the LRRK2 gene are perhaps the most common cause of familial and sporadic PD, which have been identified in approximately 3–5% of familial and 1–3% of sporadic PD cases, although the frequency may vary greatly in different populations. The LRRK2 gene encodes a rather large protein of 2527 amino acids compared with α-syn. LRRK2 contains 12 leucine-rich repeats (LRRs) in the N-terminus, a Roc domain and a MAPKKK domain in the middle, and a WD40 domain in the C-terminus. The putative kinase and GTPase activities of LRRK2 might be important in the pathogenesis of PD. In vitro studies indicate that several PD-specific mutations increase LRRK2 autophosphorylation and phosphorylation of generic protein kinase substrates. For example, the G2019S mutation at the kinase domain of LRRK2 increases its autophosphorylation by twofold. Meanwhile, a reciprocal regulation of its GTPase and kinase activities seems to influence the function and cytotoxicity of LRRK2. While LRRK2 is mainly a cytoplasmic protein, it is also partially associated with membrane organelles such as mitochondria, ER, Golgi apparatus, endosomes and synaptic vesicles. This characteristic distribution of LRRK2 may indicate an involvement of LRRK2 in membrane trafficking as suggested by findings in transgenic mouse models.
A variety of transgenic mice have been generated to study the function of LRRK2. However, none of these LRRK2 transgenic mice have developed PD-like neuropathology, such as formation of LB-like α-syn-positive inclusions and loss of SNc DA neurons. In addition, none of the LRRK2 knockout mice displayed obvious motor, behavioral or neuropathological phenotypes. By contrast, LRRK2 knockout, as well as G2019S and kinase-dead knock-in mice, developed profound pathological lesions in the periphery tissues, such as the kidney and lung of aged animals, suggesting that LRRK2 is more critically involved in maintaining the normal functions of cells in the kidney and lung, which happen to process robust secretory pathways. A further investigation of LRRK2's exact role in protein secretion and degradation in kidney and lung cells may provide significant molecular insights into the pathophysiological functions of LRRK2 in neurons and PD. Taken collectively, these observations from LRRK2 knockout and transgenic mice suggest that LRRK2 might play a rather subtle or selective role in modulating the physiological function and survival of neurons. For example, studies from primary cultured neurons derived from LRRK2 transgenic and knockout mice demonstrate an involvement of LRRK2 in axon and dendrite outgrowth during neuronal development, likely through regulating the dynamics of actin assembly or ER/Golgi vesicle trafficking.
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