Biology subjects

Devireddy, S.

Publications and source records attributed to Devireddy, S..

3 recordsLinked to original sources

bioRxiv2025

LRP10 promotes trafficking of progranulin and prosaposin to lysosomes

Mutations in LRP10, a low-density lipoprotein receptor family member, cause familial Parkinsons disease and dementia with Lewy bodies. However, its direct cellular functions remain largely undefined. Using a multidisciplinary approach, our new data shows that LRP10 is required for the efficient trafficking of progranulin and prosaposin to lysosomes. Loss of LRP10 resulted in aberrant Golgi accumulations of progranulin and prosaposin and their reduced abundance in lysosomes. Disease-linked LRP10 missense mutations failed to support this lysosomal trafficking. Moreover, LRP10 KO mice developed striking microgliosis marked by enlarged and hyper-ramified microglia, accompanied by progranulin accumulation in the Golgi. Our results define LRP10 as a positive regulator of progranulin and prosaposin lysosomal protein trafficking and microglia homeostasis and thus shed new light on how its dysfunction may drive neurodegeneration in Parkinsons Disease and dementia with Lewy bodies.

cell biology↗

bioRxiv2021

Surf4 Promotes Endoplasmic Reticulum Exit of the Lysosomal Prosaposin-Progranulin Complex

Progranulin is a lysosomal protein whose haploinsufficiency causes frontotemporal dementia while homozygous loss of progranulin causes neuronal ceroid lipofuscinosis, a lysosomal storage disease. The sensitivity of cells to progranulin deficiency raises important questions about how cells coordinate intracellular trafficking of progranulin to ensure its efficient delivery to lysosomes. In this study, we discover that progranulin interacts with prosaposin, another lysosomal protein, within the lumen of the endoplasmic reticulum (ER) and that prosaposin is required for the efficient ER exit of progranulin. Mechanistically, we identify an interaction between prosaposin and Surf4, a receptor that promotes loading of lumenal cargos into COPII coated vesicles, and establish that Surf4 is critical for the efficient export of progranulin and prosaposin from the ER. Collectively, this work demonstrates a network of interactions occurring early in the secretory pathway that promote the ER exit and subsequent lysosomal delivery of newly translated progranulin and prosaposin.

cell biology↗

bioRxiv2018

UNC-16/JIP3 and UNC-76/FEZ1 limit the density of mitochondria in C. elegans neurons by maintaining the balance of anterograde and retrograde mitochondrial transport

We investigate the role of axonal transport in regulating neuronal mitochondrial density. We show that the density of mitochondria in the touch receptor neuron (TRN) of adult Caenorhabditis elegans is constant. Mitochondrial density and transport are controlled both by the Kinesin heavy chain and the Dynein-Dynactin complex. However, unlike in other models, the presence of mitochondria in C. elegans TRNs depends on Kinesin light chain as well. Mutants in the three C. elegans miro genes do not alter mitochondrial density in the TRNs. Mutants in the Kinesin-1 associated proteins, UNC-16/JIP3 and UNC-76/FEZ1, show increased mitochondrial density and also have elevated levels of both the Kinesin Heavy and Light Chains in neurons. Genetic analyses suggest that, the increased mitochondrial density at the distal end of the neuronal process in unc-16 and unc-76 depends partly on Dynein. We observe a net anterograde bias in the ratio of anterograde to retrograde mitochondrial flux in the neuronal processes of unc-16 and unc-76, likely due to both increased Kinesin-1 and decreased Dynein in the neuronal processes. Our study shows that UNC-16 and UNC-76 indirectly limit mitochondrial density in the neuronal process maintaining a balance in anterograde and retrograde mitochondrial axonal transport.

genetics↗