Parkin deficiency delays motor decline and disease manifestation in a mouse model of synucleinopathy
PLoS One. 2009 Aug 14;4(8):e6629.
|Type of Publication:
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.