Neurology and Neuromuscular Disorders

Biography

Biography: David Boyer Ramsden

Abstract

Statement of the Problem: Mutations in leucine-rich repeat kinase 2 (LRRK2) are associated with familial and sporadic PD. How LRRK2 interacts with synaptic proteins, and its role in dopamine (DA) homeostasis, synaptic vesicle recycling and α-synuclein catabolism are unclear.

Methods: To explore the pathogenic effects of LRRK2 mutation, we generated C57BL/6N mice with homozygous LRRK2R1441G knock in (KI).

Findings: Although no abnormal phenotype was observed in mutant LRRK2R1441G mice, the KI mutation increased vulnerability to reserpine-induced striatal DA depletion and perturbed DA homeostasis resulting in presynaptic dysfunction and locomotor deficits. Subsequently, we found that mutant primary cortical and mesencephalic dopaminergic neurons were more susceptible to rotenone-induced ATP deficiency. Compared with wild-type controls, striatal synaptosomes isolated from young mutant mice exhibited significantly lower dopamine uptake after rotenone toxicity, due to reduced striatal synaptosomal mitochondria and synaptic vesicular proton pump protein (V-ATPase H) levels. Mutant mice developed greater locomotor deficits in open-field tests than wild-type mice following low oral rotenone doses given twice weekly over 50 weeks (half their lifespan). The increased locomotor deficit was associated with specific reduction in striatal mitochondrial complex-I (NDUFS4) in rotenone-treated mutant mice. Finally, we showed greater age-dependent increases of striatal oligomeric α-synuclein (toxic species) in KI mice compared to wild-type (WT). Given that a significant proportion of cellular α-synuclein is metabolized via lysosomal degradation, such accumulation of its oligomers may be a result of an age-dependent decrease in chaperone-mediated autophagy (CMA) activity associated with impaired assembly/disassembly of multimeric lamp2a translocation complexes.

Conclusion: Enhancement of CMA represents a potential treatment for PD.