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Nigrostriatal pathology with reduced astrocytes in LRRK2 S910/S935 phosphorylation deficient knockin mice.

ABSTRACT: Leucine-rich repeat kinase 2 (LRRK2) is genetically implicated in both familial and sporadic Parkinson's disease (PD). Moreover, LRRK2 has emerged as a compelling therapeutic target for the treatment of PD. Consequently, there is much interest in understanding LRRK2 and its role in PD pathogenesis. LRRK2 is constitutively phosphorylated on two serines, S910 and S935, that are required for interaction of LRRK2 with members of the 14-3-3 family of scaffolding proteins. Pathogenic LRRK2 missense mutations impair the phosphorylation of LRRK2 at these sites, but whether this contributes to PD pathology is unclear. To better understand how loss of LRRK2 phosphorylation relates to PD pathology, we have studied double knockin mice in which Lrrk2's serine 910 and 935 have both been mutated to alanine and can therefore no longer be phosphorylated. Nigrostriatal PD pathology was assessed in adult mice, aged mice, and mice inoculated with ?-synuclein fibrils. Under all paradigms there was evidence of early PD pathology in the striatum of the knockin mice, namely alterations in dopamine regulating proteins and accumulation of ?-synuclein. Striatal pathology was accompanied by a significant decrease in the number of astrocytes in the knockin mice. Despite striatal pathology, there was no degeneration of dopamine neurons in the substantia nigra and no evidence of a PD motor phenotype in the knockin mice. Our results suggest that modulation of LRRK2 serine 910 and 935 phosphorylation sites may have implications for dopamine turnover and astrocyte function, but loss of phosphorylation at these residues is not sufficient to induce PD neurodegeneration.

SUBMITTER: Zhao Y

PROVIDER: S-EPMC6197399 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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Nigrostriatal pathology with reduced astrocytes in LRRK2 S910/S935 phosphorylation deficient knockin mice.

Zhao Ye Y Keshiya Shikara S Atashrazm Farzaneh F Gao Jianqun J Ittner Lars M LM Alessi Dario R DR Halliday Glenda M GM Fu Yuhong Y Dzamko Nicolas N

Neurobiology of disease 20180905

Leucine-rich repeat kinase 2 (LRRK2) is genetically implicated in both familial and sporadic Parkinson's disease (PD). Moreover, LRRK2 has emerged as a compelling therapeutic target for the treatment of PD. Consequently, there is much interest in understanding LRRK2 and its role in PD pathogenesis. LRRK2 is constitutively phosphorylated on two serines, S910 and S935, that are required for interaction of LRRK2 with members of the 14-3-3 family of scaffolding proteins. Pathogenic LRRK2 missense mu ...[more]

PMID: 30194047

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Project description:Cognitive dysfunction is one of the most severe nonmotor symptoms of nigrostriatal impairment. This occurs as a result of profound functional and morphological changes of different neuronal circuits, including modifications in the plasticity and architecture of hippocampal synapses. Such alterations can be implicated in the genesis and progression of dementia associated with neurodegenerative diseases including Parkinson-like symptoms. There are few studies regarding cognitive changes in nigrostriatal animal models. The aim of this study was to characterize the onset of memory deficit after induction of neurotoxicity with 6-hydroxydopamine (6-OHDA) and its correlation with hippocampal dysfunction. For this, we bilaterally microinjected 6-OHDA in dorsolateral Caudate-Putamen unit (CPu) and then, animals were tested weekly for working memory, spatial short-term memory, and motor performance. We evaluated tyrosine hydroxylase (TH) as a dopamine marker, aldehyde dehydrogenase 2 (ALDH2), a mitochondria detoxification enzyme and astrocyte glial fibrillar acid protein (GFAP) an immunoreactivity marker involved in different areas: CPu, substantia nigra, prefrontal cortex, and hippocampus. We observed a specific prefrontal cortex and nigrostriatal pathway TH reduction while ALDH2 showed a decrease-positive area in all the studied regions. Moreover, GFAP showed a specific CPu decrease and hippocampus increase of positively stained area on the third week after toxicity. We also evaluated the threshold to induce long-term potentiation in hippocampal excitability. Our findings showed that reduced hippocampal synaptic transmission was accompanied by deficits in memory processes, without affecting motor performance on the third-week post 6-OHDA administration. Our results suggest that 3 weeks after neurotoxic administration, astrocytes and ALDH2 mitochondrial enzyme modifications participate in altering the properties that negatively affect hippocampal function and consequently cognitive behavior.

Dataset Information

Nigrostriatal pathology with reduced astrocytes in LRRK2 S910/S935 phosphorylation deficient knockin mice.

Publications

Nigrostriatal pathology with reduced astrocytes in LRRK2 S910/S935 phosphorylation deficient knockin mice.

Similar Datasets

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