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A cell autonomous torsinA requirement for cholinergic neuron survival and motor control.

ABSTRACT: Cholinergic dysfunction is strongly implicated in dystonia pathophysiology. Previously (Pappas et al., 2015;4:e08352), we reported that Dlx5/6-Cre mediated forebrain deletion of the DYT1 dystonia protein torsinA (Dlx-CKO) causes abnormal twisting and selective degeneration of dorsal striatal cholinergic interneurons (ChI) (Pappas et al., 2015). A central question raised by that work is whether the ChI loss is cell autonomous or requires torsinA loss from neurons synaptically connected to ChIs. Here, we addressed this question by using ChAT-Cre mice to conditionally delete torsinA from cholinergic neurons ('ChAT-CKO'). ChAT-CKO mice phenocopy the Dlx-CKO phenotype of selective dorsal striatal ChI loss and identify an essential requirement for torsinA in brainstem and spinal cholinergic neurons. ChAT-CKO mice are tremulous, weak, and exhibit trunk twisting and postural abnormalities. These findings are the first to demonstrate a cell autonomous requirement for torsinA in specific populations of cholinergic neurons, strengthening the connection between torsinA, cholinergic dysfunction and dystonia pathophysiology.

SUBMITTER: Pappas SS

PROVIDER: S-EPMC6115190 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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A cell autonomous torsinA requirement for cholinergic neuron survival and motor control.

Pappas Samuel S SS Li Jay J LeWitt Tessa M TM Kim Jeong-Ki JK Monani Umrao R UR Dauer William T WT

eLife 20180817

Cholinergic dysfunction is strongly implicated in dystonia pathophysiology. Previously (Pappas et al., 2015;4:e08352), we reported that Dlx5/6-Cre mediated forebrain deletion of the DYT1 dystonia protein torsinA (Dlx-CKO) causes abnormal twisting and selective degeneration of dorsal striatal cholinergic interneurons (ChI) (Pappas et al., 2015). A central question raised by that work is whether the ChI loss is cell autonomous or requires torsinA loss from neurons synaptically connected to ChIs. H ...[more]

PMID: 30117805

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Project description:Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common genetic cause of Parkinson's disease (PD), which is the leading neurodegenerative movement disorder characterized by the progressive loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc). However, whether LRRK2 mutations cause PD and degeneration of DA neurons via a toxic gain-of-function or a loss-of-function mechanism is unresolved and has pivotal implications for LRRK2-based PD therapies. In this study, we investigate whether LRRK2 and its functional homologue LRRK1 play an essential, intrinsic role in DA neuron survival through the development of DA neuron-specific LRRK conditional double knockout (cDKO) mice. We first generated and characterized floxed LRRK1 and LRRK2 mice and then confirmed that germline deletions of the floxed LRRK1 and LRRK2 alleles result in null mutations, as evidenced by the absence of LRRK1 and LRRK2 mRNA and protein in the respective homozygous deleted mutant mice. We further examined the specificity of Cre-mediated recombination driven by the dopamine transporter-Cre (DAT-Cre) knockin (KI) allele using a GFP reporter line and confirmed that DAT-Cre-mediated recombination is restricted to DA neurons in the SNpc. Crossing these validated floxed LRRK1 and LRRK2 mice with DAT-Cre KI mice, we then generated DA neuron-restricted LRRK cDKO mice and further showed that levels of LRRK1 and LRRK2 are reduced in dissected ventral midbrains of LRRK cDKO mice. While DA neuron-restricted LRRK cDKO mice of both sexes exhibit normal mortality and body weight, they develop age-dependent loss of DA neurons in the SNpc, as demonstrated by the progressive reduction of DA neurons in the SNpc of LRRK cDKO mice at the ages of 20 and 24 months but the unaffected number of DA neurons at the age of 15 months. Moreover, DA neurodegeneration is accompanied with increases of apoptosis and elevated microgliosis in the SNpc as well as decreases of DA terminals in the striatum, and is preceded by impaired motor coordination. Taken together, these findings provide the unequivocal evidence for the importance of LRRK in DA neurons and raise the possibility that LRRK2 mutations may impair its protection of DA neurons, leading to DA neurodegeneration in PD.

Dataset Information

A cell autonomous torsinA requirement for cholinergic neuron survival and motor control.

Publications

A cell autonomous torsinA requirement for cholinergic neuron survival and motor control.

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