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Perturbations in endo-lysosomal trafficking pathways are linked to many neurodevelopmental and neurodegenerative diseases. Of relevance to our current study, MAPK8IP3/JIP3, a brain enriched putative adaptor between lysosomes and motors has been previously implicated as a key regulator of axonal lysosome transport. Since de novo variants in MAPK8IP3 have recently been linked to a neurodevelopmental disorder with intellectual disability, there is a need to better understand the functioning of this protein in human neurons. To this end, using induced neurons (i3Neurons) derived from human iPSCs lacking MAPK8IP3, we demonstrate that loss of hMAPK8IP3 affects endocytic uptake in neurons but does not affect the proteolytic activity of lysosomes in neuronal cell bodies. Our findings indicate that MAPK8IP3 may be a regulator of bulk endocytosis in neurons and that altered endocytic uptake may play a role in MAPK8IP3-linked neurodevelopmental disorders. [ABSTRACT FROM AUTHOR]

Lysosomal storage diseases (LSDs) with neurological involvement are inherited genetic diseases of the metabolism characterized by lysosomal dysfunction and the accumulation of undegraded substrates altering glial and neuronal function. Often, patients with neurological manifestations present with damage to the gray and white matter and irreversible neuronal decline. The use of animal models of LSDs has greatly facilitated studying and identifying potential mechanisms of neuronal dysfunction, including alterations in availability and function of synaptic proteins, modifications of membrane structure, deficits in docking, exocytosis, recycling of synaptic vesicles, and inflammation-mediated remodeling of synapses. Although some extrapolations from findings in adult-onset conditions such as Alzheimer's disease or Parkinson's disease have been reported, the pathogenetic mechanisms underpinning cognitive deficits in LSDs are still largely unclear. Without being fully inclusive, the goal of this mini-review is to present a discussion on possible mechanisms leading to synaptic dysfunction in LSDs. [ABSTRACT FROM AUTHOR]