Abstract
Vps35 (vacuolar protein sorting 35) is a key component of retromer that regulates transmembrane protein trafficking. Dysfunctional Vps35 is a risk factor for neurodegenerative diseases, including Parkinson’s and Alzheimer’s diseases. Vps35 is highly expressed in developing pyramidal neurons, and its physiological role in developing neurons remains to be explored. Here, we provide evidence that Vps35 in embryonic neurons is necessary for axonal and dendritic terminal differentiation. Loss of Vps35 in embryonic neurons results in not only terminal differentiation deficits, but also neurodegenerative pathology, such as cortical brain atrophy and reactive glial responses. The atrophy of neocortex appears to be in association with increases in neuronal death, autophagosome proteins (LC3-II and P62), and neurodegeneration associated proteins (TDP43 and ubiquitin-conjugated proteins). Further studies reveal an increase of retromer cargo protein, sortilin1 (Sort1), in lysosomes of Vps35-KO neurons, and lysosomal dysfunction. Suppression of Sort1 diminishes Vps35-KO-induced dendritic defects. Expression of lysosomal Sort1 recapitulates Vps35-KO-induced phenotypes. Together, these results demonstrate embryonic neuronal Vps35’s function in terminal axonal and dendritic differentiation, reveal an association of terminal differentiation deficit with neurodegenerative pathology, and uncover an important lysosomal contribution to both events.
Highlights
Neurodegenerative diseases, including Alzheimer’s disease (AD), Parkinson’s disease (PD), and frontotemporal dementia (FTD), occur as a result of complex brain degenerative processes with a progressive loss of neurons or brain structures [1]
Cre-encoding plasmids were electroporated into the neural stem cells (NSCs) or neural progenitor cells (NPCs) in the ventricular zone of Vps35f/f embryos at E14.5
At P7, most of Vps35KO (Cre-GFP+) neurons had migrated to neocortical L2–3, as that of control (GFP+) neurons (Fig. 1b)
Summary
Neurodegenerative diseases, including Alzheimer’s disease (AD), Parkinson’s disease (PD), and frontotemporal dementia (FTD), occur as a result of complex brain degenerative processes with a progressive loss of neurons or brain structures [1]. Mice that selectively depleted Vps gene in embryonic (by Neurod6-Cre) pyramidal neurons display FTD-like neuropathology, including progressive reduction of cortical thickness, elevation of cortical neuronal death, accumulations of P62, LC3-II, Tdp, and ubiquitin-conjugated protein levels, impairments in lysosomal morphology and acidification, and reactive gliosis. Expression of lysosomal Sort fusion protein in embryonic pyramidal neurons impairs lysosomal functions and recapitulates Vps35-loss-induced deficits. These observations uncover Sort as a critical cargo of Vps to underlie Vps35’s function in developing neurons. Our results suggest that the dysfunctional Vps35-Sort pathway in developing pyramidal neurons acts as a detrimental factor for neuronal terminal differentiation and for neurodegenerative pathology. To test the pH in lysosomes, Lyso-pHluorin (Plasmid #70113) were obtained via Addgene, and the promoter CMV was replaced with CAG
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