Lab Research: Lysosomal Biology & Neurodegeneration
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2026Preprint
Welch M, Sampognaro PJ, Shu S, Chaplot K, Bothra A, Castruita PA, Smith AW, Antee T, Hodul M, Tian R, Gao V, Limas JC, Burris KD, Parker JL, Yokoyama JS, Miller BL, Seeley WW, Newstead S, Kampmann M, Kao AW. A neuronal CRISPRi screen identifies PQLC2 as a lysosomal pH regulator controlling tau homeostasis. bioRxiv. Posted August 28, 2026.
Key finding: a genome-wide CRISPRi screen in human neurons identifies the lysosomal amino acid exporter PQLC2 as a regulator of lysosomal acidification, independent of its transport function. A PQLC2 variant identified in tauopathy impairs acidification and increases tau accumulation. -
2026
Ackley C, Liau Z, Arya S, Antee T, Cheang E, Knudsen GM, Lane-Donovan C, Sampognaro PJ, Kao AW. Lysosomal protease-mediated APP degradation is pH-dependent, mutation-sensitive, and facilitates tau proteolysis. Mol Neurodegener Adv. 2026;2(1):10.
Key finding: maps the sites where lysosomal cathepsins cleave APP and shows that several of these cleavages are sensitive to pH and to the pathogenic variants E693G and E693Q. Soluble APP also enhances cleavage of tau by cathepsin G. -
2026
Hodul M, Lane-Donovan C, Cheang ES, Gao V, Sampognaro PJ, Mambou EA, Yang Z, Kao AW. Prosaposin Is Cleaved Into Saposins by Multiple Cathepsins in a Progranulin-Regulated Fashion. J Neurochem. 2026 Jan;170(1):e70357.
Key finding: identifies the lysosomal proteases that cleave prosaposin into saposins, which drive sphingolipid breakdown, including several cathepsins not previously known to process it. Progranulin and multi-granulin fragments directly regulate prosaposin cleavage by cathepsin D. -
2024
Babu S, Nicholson KA, Rothstein JD, Swenson A, Sampognaro PJ, Pant P, Macklin EA, Spruill S, Paganoni S, Gendron TF, Prudencio M, Petrucelli L, Nix D, Landrette S, Nkrumah E, Fandrick K, Edwards J, Young PR. Apilimod dimesylate in C9orf72 amyotrophic lateral sclerosis: a randomized phase 2a clinical trial. Brain. 2024 Sep 3;147(9):2998-3008.
Key finding: in a randomized, placebo-controlled phase 2a trial in people with C9orf72 ALS, the PIKfyve inhibitor apilimod was safe, reached the CSF, and lowered CSF poly(GP), a C9orf72 dipeptide repeat protein, by 73%. -
2023
Sampognaro PJ, Arya S, Knudsen GM, et al. Mutations in α-synuclein, TDP-43 and tau prolong protein half-life through diminished degradation by lysosomal proteases. Mol Neurodegener. 2023;18(1):29.
Key finding: pathogenic mutations in α-synuclein, TDP-43, and tau disrupt lysosomal protease cleavage sites, so the mutant proteins are degraded less efficiently and persist longer in cells. This suggests a shared mechanism across synucleinopathies, TDP-43 proteinopathies, and tauopathies. -
2021
Mohan S, Sampognaro PJ, Argouarch AR, Maynard JC, Welch M, Patwardhan A, Courtney EC, Zhang J, Mason A, Li KH, Huang EJ, Seeley WW, Miller BL, Burlingame A, Jacobson MP, Kao AW. Processing of progranulin into granulins involves multiple lysosomal proteases and is affected in frontotemporal lobar degeneration. Mol Neurodegener. 2021;16:51.
Key finding: identifies multiple lysosomal proteases that process progranulin into granulins, including a new role for asparagine endopeptidase (AEP) in releasing granulin F. Brain tissue from people with progranulin-related FTLD showed increased granulin F and AEP activity in affected regions. -
2020
Gururaj S, Sampognaro PJ, Argouarch AR, Kao AW. Progranulin Adsorbs to Polypropylene Tubes and Disrupts Functional Assays: Implications for Research, Biomarker Studies, and Therapeutics. Front Neurosci. 2020 Dec 14;14:602235.
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2019
Sloan EA, Sampognaro PJ, Junn JC, Chin C, Jacques L, Ramachandran PS, DeRisi JL, Wilson MR, Kriegstein AR, Bollen AW, Solomon DA, Margeta M, Engstrom JW. Neuroglial stem cell-derived inflammatory pseudotumor (n-SCIPT): clinicopathologic characterization of a novel lesion of the lumbosacral spinal cord and nerve roots following intrathecal allogeneic stem cell intervention. Acta Neuropathol. 2019 Dec;138(6):1103-1106.
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2019
Sampognaro PJ, Vatsavayai SC, Cosme CG, Hwang JL, Nolan A, Huang EJ, Seeley WW, De May MG. C9orf72-specific phenomena associated with frontotemporal dementia and gastrointestinal symptoms in the absence of TDP-43 aggregation. Acta Neuropathol. 2019 Dec;138(6):1093-1097.
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2014
Clifford MA, Athar W, Leonard CE, Russo A, Sampognaro PJ, Van der Goes MS, Burton DA, Zhao X, Lalchandani RR, Sahin M, Vicini S, Donoghue MJ. EphA7 signaling guides cortical dendritic development and spine maturation. Proc Natl Acad Sci U S A. 2014 Apr 1;111(13):4994-9.
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2012
Bricceno KV, Sampognaro PJ, Van Meerbeke JP, Sumner CJ, Fischbeck KH, Burnett BG. Histone deacetylase inhibition suppresses myogenin-dependent atrogene activation in spinal muscular atrophy mice. Hum Mol Genet. 2012 Oct 15;21(20):4448-59.
Earlier Work & Case Reports
From Dr. Sampognaro's residency and medical school years, outside the lab's current research focus.
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2019
Deng H, Yue JK, Sampognaro PJ, Rosendale N. Acute Sensorimotor Deficit as a Lone Manifestation of Neurocysticercosis: An Important Differential Diagnosis in Emergency Departments of Developed Countries. J Glob Infect Dis. 2019 Jan-Mar;11(1):50-51.
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2013
Sampognaro PJ, Mitchell SL, Weeks SR, Khalifian S, Markman TM, Uebel LW, Dattilo JR. Medical student appraisal: electronic resources for inpatient pre-rounding. Appl Clin Inform. 2013 Aug 28;4(3):403-18.
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2013
Markman TM, Sampognaro PJ, Mitchell SL, Weeks SR, Khalifian S, Dattilo JR. Medical student appraisal: applications for bedside patient education. Appl Clin Inform. 2013 Apr 24;4(2):201-11.