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Loss of the parkinsonism-associated protein FBXO7 in glutamatergic forebrain neurons in mice leads to anormal motor behavior and synaptic defects

ABSTRACT: Mutations in PARK15, which encodes for the F-box protein FBXO7 have been associated with Parkinsonian Pyramidal syndrome, a rare and complex movement disorder with Parkinsonian symptoms, pyramidal tract signs and juvenile onset. Our previous study showed that systemic loss of Fbxo7 in mice causes motor defects and premature death. We have also demonstrated that FBXO7 has a crucial role in neurons as the specific deletion in tyrosine hydroxylase-positive or glutamatergic forebrain neurons leads to late-onset or early-onset motor dysfunction, respectively. In this study, we examined NEXCre; Fbxo7fl/fl mice, in which Fbxo7 was specifically deleted in glutamatergic projection neurons. The effects of FBXO7 deficiency on striatal integrity were investigated with HPLC and histological analyses. NEX-Cre;Fbxo7fl/fl mice revealed an increase in striatal dopamine concentrations, changes in the glutamatergic, GABAergic and dopaminergic pathways, astrogliosis and microgliosis and little or no neuronal loss in the striatum. To determine the effects on the integrity of the synapse, we purified synaptic membranes, subjected them to quantitative mass spectrometry analysis and found alterations in the complement system, endocytosis and exocytosis pathways. These neuropathological changes coincide with alterations in spontaneous home cage behavior. Taken together, our findings suggest that FBXO7 is crucial for corticostriatal projections and the synaptic integrity of the striatum, and consequently for proper motor control.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Brain

DISEASE(S): Parkinson's Disease

SUBMITTER: Christian Preisinger

LAB HEAD: Judith Stegmüller

PROVIDER: PXD044119 | Pride | 2023-09-18

REPOSITORIES: Pride

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	OR2_2019_02_03_JS_ko1_1.raw	Raw
	OR2_2019_02_03_JS_ko1_2.raw	Raw
	OR2_2019_02_03_JS_ko1_3.raw	Raw
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Loss of the parkinsonism-associated protein FBXO7 in glutamatergic forebrain neurons in mice leads to anormal motor behavior and synaptic defects

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