Parkin deficiency delays motor decline and disease manifestation in a mouse model of synucleinopathy.

In synucleinopathies, including Parkinson's disease, partially
ubiquitylated alpha-synuclein species phosphorylated on serine 129
(P(S129)-alpha-synuclein) accumulate abnormally. Parkin, an
ubiquitin-protein ligase that is dysfunctional in autosomal
recessive parkinsonism, protects against alpha-synuclein-mediated
toxicity in various models.We analyzed the effects of Parkin
deficiency in a mouse model of synucleinopathy to explore the
possibility that Parkin and alpha-synuclein act in the same
biochemical pathway. Whether or not Parkin was present, these mice
developed an age-dependent neurodegenerative disorder preceded by a
progressive decline in performance in tasks predictive of
sensorimotor dysfunction. The symptoms were accompanied by the
deposition of P(S129)-alpha-synuclein but not
P(S87)-alpha-synuclein in neuronal cell bodies and neuritic
processes throughout the brainstem and the spinal cord; activation
of caspase 9 was observed in 5% of the
P(S129)-alpha-synuclein-positive neurons. As in Lewy bodies,
ubiquitin-immunoreactivity, albeit less abundant, was invariably
co-localized with P(S129)-alpha-synuclein. During late disease
stages, the disease-specific neuropathological features revealed by
ubiquitin- and P(S129)-alpha-synuclein-specific antibodies were
similar in mice with or without Parkin. However, the proportion of
P(S129)-alpha-synuclein-immunoreactive neuronal cell bodies and
neurites co-stained for ubiquitin was lower in the absence than in
the presence of Parkin, suggesting less advanced synucleinopathy.
Moreover, sensorimotor impairment and manifestation of the
neurodegenerative phenotype due to overproduction of human
alpha-synuclein were significantly delayed in Parkin-deficient
mice.These findings raise the possibility that effective
compensatory mechanisms modulate the phenotypic expression of
disease in parkin-related parkinsonism.