Dataset Information

Synj1 haploinsufficiency causes dopamine neuron vulnerability and alpha-synuclein accumulation in mice.

ABSTRACT: Synaptojanin1 (synj1) is a phosphoinositide phosphatase with dual SAC1 and 5'-phosphatase enzymatic activities in regulating phospholipid signaling. The brain-enriched isoform has been shown to participate in synaptic vesicle (SV) recycling. More recently, recessive human mutations were identified in the two phosphatase domains of SYNJ1, including R258Q, R459P and R839C, which are linked to rare forms of early-onset Parkinsonism. We now demonstrate that Synj1 heterozygous deletion (Synj1+/-), which is associated with an impaired 5'-phosphatase activity, also leads to Parkinson's disease (PD)-like pathologies in mice. We report that male Synj1+/- mice display age-dependent motor function abnormalities as well as alpha-synuclein accumulation, impaired autophagy and dopaminergic terminal degeneration. Synj1+/- mice contain elevated 5'-phosphatase substrate, PI(4,5)P2, particularly in the midbrain neurons. Moreover, pharmacological elevation of membrane PI(4,5)P2 in cultured neurons impairs SV endocytosis, specifically in midbrain neurons, and further exacerbates SV trafficking defects in Synj1+/- midbrain neurons. We demonstrate down-regulation of SYNJ1 transcript in a subset of sporadic PD brains, implicating a potential role of Synj1 deficiency in the decline of dopaminergic function during aging.

SUBMITTER: Pan PY

PROVIDER: S-EPMC7424763 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Synj1 haploinsufficiency causes dopamine neuron vulnerability and alpha-synuclein accumulation in mice.

Pan Ping-Yue PY Sheehan Patricia P Wang Qian Q Zhu Xinyu X Zhang Yuanxi Y Choi Insup I Li Xianting X Saenz Jacqueline J Zhu Justin J Wang Jing J El Gaamouch Farida F Zhu Li L Cai Dongming D Yue Zhenyu Z

Human molecular genetics 20200801 14

Synaptojanin1 (synj1) is a phosphoinositide phosphatase with dual SAC1 and 5'-phosphatase enzymatic activities in regulating phospholipid signaling. The brain-enriched isoform has been shown to participate in synaptic vesicle (SV) recycling. More recently, recessive human mutations were identified in the two phosphatase domains of SYNJ1, including R258Q, R459P and R839C, which are linked to rare forms of early-onset Parkinsonism. We now demonstrate that Synj1 heterozygous deletion (Synj1+/-), wh ...[more]

PMID: 32356558

Similar Datasets

Project description:Alpha-synuclein (α-syn) mislocalization and accumulation in intracellular inclusions is the major pathological hallmark of degenerative synucleinopathies, including Parkinson's disease, Parkinson's disease with dementia and dementia with Lewy bodies. Typical symptoms are behavioural abnormalities including motor deficits that mark disease progression, while non-motor symptoms and synaptic deficits are already apparent during the early stages of disease. Synucleinopathies have therefore been considered synaptopathies that exhibit synaptic dysfunction prior to neurodegeneration. However, the mechanisms and events underlying synaptopathy are largely unknown. Here we investigated the cascade of pathological events underlying α-syn accumulation and toxicity in a Drosophila model of synucleinopathy by employing a combination of histological, biochemical, behavioural and electrophysiological assays. Our findings demonstrate that targeted expression of human α-syn leads to its accumulation in presynaptic terminals that caused downregulation of synaptic proteins, cysteine string protein, synapsin, and syntaxin 1A, and a reduction in the number of Bruchpilot puncta, the core component of the presynaptic active zone essential for its structural integrity and function. These α-syn-mediated presynaptic alterations resulted in impaired neuronal function, which triggered behavioural deficits in ageing Drosophila that occurred prior to progressive degeneration of dopaminergic neurons. Comparable alterations in presynaptic active zone protein were found in patient brain samples of dementia with Lewy bodies. Together, these findings demonstrate that presynaptic accumulation of α-syn impairs the active zone and neuronal function, which together cause synaptopathy that results in behavioural deficits and the progressive loss of dopaminergic neurons. This sequence of events resembles the cytological and behavioural phenotypes that characterise the onset and progression of synucleinopathies, suggesting that α-syn-mediated synaptopathy is an initiating cause of age-related neurodegeneration.

Dataset Information

Synj1 haploinsufficiency causes dopamine neuron vulnerability and alpha-synuclein accumulation in mice.

Publications

Synj1 haploinsufficiency causes dopamine neuron vulnerability and alpha-synuclein accumulation in mice.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets