Mechanisms of LRRK2-dependent neurodegeneration: role of enzymatic activity and protein aggregation

Abstract

Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are the most common cause of familial Parkinson’s disease (PD) with autosomal dominant inheritance. Accordingly, LRRK2 has emerged as a promising therapeutic target for disease modification in PD. Since the first discovery of LRRK2 mutations some 12 years ago, LRRK2 has been the subject of intense investigation. It has been established that LRRK2 can function as a protein kinase, with many putative substrates identified, and can also function as a GTPase that may serve in part to regulate kinase activity. Familial mutations influence both of these enzymatic activities, suggesting that they may be important for the development of PD. Many LRRK2 models have been established to understand the pathogenic effects and mechanisms of familial mutations. Here, we provide a focused discussion of the evidence supporting a role for kinase and GTPase activity in mediating the pathogenic effects of familial LRRK2 mutations in different model systems, with an emphasis on rodent models of PD. We also critically discuss the contribution and relevance of protein aggregation, namely of α-synuclein and tau-proteins, which are known to form aggregates in PD brains harboring LRRK2 mutations, to neurodegeneration in LRRK2 rodent models. We aim to provide a clear and unbiased review of some of the key mechanisms that are important for LRRK2-dependent neurodegeneration in PD.

New Developments in Genetic rat models of Parkinson's Disease

“…LRRK2 is a large ∼286‐kDa protein, with multiple domains including enzymatically functional kinase and GTPase domains. It is highly unusual for a single polypeptide to contain both kinase and GTPase activities, which suggests these activities are crucially linked in the regulation or function of LRRK2 . In vitro studies show that PD‐linked LRRK2 mutations increase LRRK2 kinase activity, which is required for LRRK2‐mediated cell toxicity .…”

“…It is highly unusual for a single polypeptide to contain both kinase and GTPase activities, which suggests these activities are crucially linked in the regulation or function of LRRK2. [76][77][78] In vitro studies show that PD-linked LRRK2 mutations increase LRRK2 kinase activity, which is required for LRRK2-mediated cell toxicity. [79][80][81] LRRK2-KO rats have no obvious phenotype but are surprisingly resistant to nigral dopaminergic neuron loss induced by adeno-associated viral (AAV) expression of wild-type human a-synuclein.…”

Dopaminergic Neurodegeneration Induced by Parkinson’s Disease-Linked G2019S LRRK2 is Dependent on Kinase and GTPase Activity

“…LRRK2 is a large multi-domain protein containing two central enzymatic domains, a Ras-of-Complex (Roc) GTPase domain and a tyrosine kinase-like kinase domain, linked by a C-terminal-of-Roc (COR) domain and flanked by four protein interaction repeat domains (12). Familial PD-linked mutations cluster within the Roc-COR tandem (N1437H, R1441C/G/H, R1628P and Y1699C) and kinase (I2012T, G2019S and I2020T) domains of LRRK2 suggesting important roles for both enzymatic activities in the pathophysiology of PD.…”

“…Due to this adverse impact on LRRK2 protein levels, the neuroprotective effects of genetically inhibiting kinase activity or GTP-binding in neuronal models based upon PD-linked LRRK2 mutants have been difficult to robustly demonstrate. Notwithstanding these concerns, it is generally accepted that neuronal toxicity in primary culture models induced by mutant LRRK2 is mediated via a kinasedependent mechanism whereas the contribution of GTPase activity is less certain (12).…”

“…The molecular mechanisms underlying the pathogenic effects of familial LRRK2 mutations in the mammalian brain are poorly understood due largely to the lack of robust neurodegenerative phenotypes in most animal models (33). While certain transgenic mouse models with high-level overexpression of mutant LRRK2 can develop a modest yet late-onset loss of substantia nigra dopaminergic neurons (34)(35)(36), these models are generally the exception, with most LRRK2 transgenic or knockin models of PD developing only subtle if any neuropathology over their lifespan (12,33). Viral-mediated gene transfer in the rodent brain using large-capacity vectors such as a herpes simplex virus (HSV) amplicon or human adenovirus serotype 5 (Ad5) has been successful in producing models with robust and progressive dopaminergic neurodegeneration induced by human G2019S LRRK2, occurring over a shorter more feasible timeframe i.e.…”