Parkinson’s disease-linked D620N VPS35 knockin mice manifest tau neuropathology and dopaminergic neurodegeneration

Abstract

Mutations in thevacuolar protein sorting 35 ortholog(VPS35) gene represent a cause of late-onset, autosomal dominant familial Parkinson’s disease (PD). A single missense mutation, D620N, is considered pathogenic based upon its segregation with disease in multiple families with PD. At present, the mechanism(s) by which familialVPS35mutations precipitate neurodegeneration in PD are poorly understood. Here, we employ a germlineD620N VPS35knockin (KI) mouse model of PD to formally establish the age-related pathogenic effects of the D620N mutation at physiological expression levels. Our data demonstrate that a heterozygous or homozygous D620N mutation is sufficient to reproduce key neuropathological hallmarks of PD as indicated by the progressive degeneration of nigrostriatal pathway dopaminergic neurons and widespread axonal pathology. Unexpectedly, endogenous D620N VPS35 expression induces robust tau-positive somatodendritic pathology throughout the brain as indicated by abnormal hyperphosphorylated and conformation-specific tau, which may represent an important and early feature of mutant VPS35-induced neurodegeneration in PD. In contrast, we find no evidence for α-synuclein–positive neuropathology in agedVPS35KI mice, a hallmark of Lewy body pathology in PD. D620N VPS35 expression also fails to modify the lethal neurodegenerative phenotype of human A53T-α-synuclein transgenic mice. Finally, by crossingVPS35KI and null mice, our data demonstrate that a singleD620N VPS35allele is sufficient for survival and early maintenance of dopaminergic neurons, indicating that the D620N VPS35 protein is fully functional. Our data raise the tantalizing possibility of a pathogenic interplay between mutant VPS35 and tau for inducing neurodegeneration in PD.

Retromer repletion with AAV9-VPS35 restores endosomal function in the mouse hippocampus

“…Finally, our findings have therapeutic implications. They provide ‘preclinical’ validation that retromer viral vectors can be a viable gene therapy approach for late-onset AD, This may also be important for other disorders like PD, for which there is evidence that primary defects in retromer-dependent endosomal trafficking act as causal drivers of disease 28–33 . Just as importantly, our findings show that the primary effect of VPS35 overexpression is on neurons that have endosomal dysfunction, and that even in those the effect is to normalize defects induced by retromer depletion.…”

Vesicular Dysfunction and the Pathogenesis of Parkinson’s Disease: Clues From Genetic Studies

“…A key caveat to our understanding of how VPS35 mutations link to Parkinson's is that, to date, no VPS35 mutation brains have come to post-mortem pathological analysis, and therefore it is not known if VPS35 PD is a synucleinopathy. It is of interest to note that VPS35 (D620N) mutation causes tau pathology in mice (Chen et al, 2019) and its levels are reduced in two primary tauopathies progressive supranuclear palsy and Pick's disease (Vagnozzi et al, 2019).…”

Neuronal vulnerability in Parkinson disease: Should the focus be on axons and synaptic terminals?

“…In addition, other endolysosomal genes have also been linked to familial PD, including autosomal-dominant mutations in the retromer complex member, VPS35, [118][119][120] and autosomal-recessive mutations in the lysosomal cation channel, PARK9/ATP13A2. 121 More recently, lysosomal genes CTSB, GALC, TMEM175, and ATP6V0A1 have also been identified as PD risk factors.…”