The neuronal ceroid lipofuscinosis (NCLs) are recessively inherited childhood disorders, with an incidence of approximately 1:12,500 in the U.S. NCL is a problem of selectively impaired mitochondrial autophagy, as neuronal cells in the CNS feature the accumulation of ATP synthase subunit c in autofluorescent deposits. The genetic evidence leads to the hypothesis that different NCL loci regulate distinct steps in mitochondrial autophagy. Most cases of NCL (JNCL; Batten disease) are due to a genomic deletion mutation in CLN3 that disrupts battenin, an endosomal/lysosomal membrane protein implicated in pH regulation. The more severe variant late infantile (vLINCL) form of the disease is caused by mutations in CLN6. Fulfilling our previous aims, we have identified CLN6, which encodes linclin, a membrane protein that may localize to the endoplasmic reticulum (ER). In addition to different subcellular localizations, linclin and battenin associate with different sets of partner proteins. In this renewal application, we propose to use genetic vLINCL Cln6[nclf] and JNCL Cln3 [delta-ex7/8] mouse and cell culture models, which exhibit deficits observed in patient cells, to delineate the discrete steps in mitochondrial autophagy in neuronal cells that require linclin and battenin function.
Aim 1 will test the hypothesis that linclin and battenin functions in mitochondrial autophagy in wild-type neuronal cells entail activities in specialized ER and endosomal/lysosomal compartments, respectively.
Aim 2 will assess whether candidate partner proteins implicated in linclin or battenin function are required for normal mitochondrial autophagy in wild-type neuronal cells.
Aim 3 will determine whether vLINCL and JNCL mutations block different steps in mitochondrial autophagy in homozygous mutant Cln6[nclf] and Cln3[delta-ex7/8] neuronal cells.
Aim 4 will test the hypothesis that mitochondrial dysfunction may be linked to impaired mitochondrial autophagy, by identifying FDA approved compounds that may alter both abnormal phenotypes in Cln6[nclf] and Cln3[delta-ex7/8] neuronal cells. These studies are expected to uncover linclin and battenin activities in mitochondrial autophagy in neuronal cells, shedding light on the pathophysiology of JNCL and vLINCL and spurring the development of effective therapies for these devastating disorders.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Mammalian Genetics Study Section (MGN)
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Tagle, Danilo A
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Massachusetts General Hospital
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