| First Author | Geertsma HM | Year | 2022 |
| Journal | Hum Mol Genet | Volume | 31 |
| Issue | 21 | Pages | 3613-3628 |
| PubMed ID | 35179202 | Mgi Jnum | J:351405 |
| Mgi Id | MGI:7444597 | Doi | 10.1093/hmg/ddac035 |
| Citation | Geertsma HM, et al. (2022) Constitutive nuclear accumulation of endogenous alpha-synuclein in mice causes motor impairment and cortical dysfunction, independent of protein aggregation. Hum Mol Genet 31(21):3613-3628 |
| abstractText | A growing body of evidence suggests that nuclear alpha-synuclein (alphaSyn) plays a role in the pathogenesis of Parkinson's disease (PD). However, this question has been difficult to address as controlling the localization of alphaSyn in experimental systems often requires protein overexpression, which affects its aggregation propensity. To overcome this, we engineered SncaNLS mice, which localize endogenous alphaSyn to the nucleus. We characterized these mice on a behavioral, histological and biochemical level to determine whether the increase of nuclear alphaSyn is sufficient to elicit PD-like phenotypes. SncaNLS mice exhibit age-dependent motor deficits and altered gastrointestinal function. We found that these phenotypes were not linked to alphaSyn aggregation or phosphorylation. Through histological analyses, we observed motor cortex atrophy in the absence of midbrain dopaminergic neurodegeneration. We sampled cortical proteomes of SncaNLS mice and controls to determine the molecular underpinnings of these pathologies. Interestingly, we found several dysregulated proteins involved in dopaminergic signaling, including Darpp32, Pde10a and Gng7, which we further confirmed was decreased in cortical samples of the SncaNLS mice compared with controls. These results suggest that chronic endogenous nuclear alphaSyn can elicit toxic phenotypes in mice, independent of its aggregation. This model raises key questions related to the mechanism of alphaSyn toxicity in PD and provides a new model to study an underappreciated aspect of PD pathogenesis. |
