{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,5,7]],"date-time":"2026-05-07T02:06:38Z","timestamp":1778119598904,"version":"3.51.4"},"posted":{"date-parts":[[2024,5,30]]},"group-title":"Pathology","reference-count":90,"publisher":"openRxiv","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2024,5,30]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>Accumulated levels of mutant huntingtin protein (mHTT) and its fragments are considered contributors to the pathogenesis of Huntington\u2019s disease (HD). Although lowering mHTT by stimulating autophagy has been considered a possible therapeutic strategy, the role and competence of autophagy-lysosomal pathway (ALP) during HD progression in the human disease remains largely unknown. Here, we used multiplex confocal and ultrastructural immunocytochemical analyses of ALP functional markers in relation to mHTT aggresome pathology in striatum and the less affected cortex of HD brains staged from HD2 to HD4 by Vonsattel neuropathological criteria compared to controls. Immunolabeling revealed the localization of HTT\/mHTT in ALP vesicular compartments labeled by autophagy-related adaptor proteins p62\/SQSTM1 and ubiquitin, and cathepsin D (CTSD) as well as HTT-positive inclusions. Although comparatively normal at HD2, neurons at later HD stages exhibited progressive enlargement and clustering of CTSD-immunoreactive autolysosomes\/lysosomes and, ultrastructurally, autophagic vacuole\/lipofuscin granules accumulated progressively, more prominently in striatum than cortex. These changes were accompanied by rises in levels of HTT\/mHTT and p62\/SQSTM1, particularly their fragments, in striatum but not in the cortex, and by increases of LAMP1 and LAMP2 RNA and LAMP1 protein. Importantly, no blockage in autophagosome formation and autophagosome-lysosome fusion was detected, thus pinpointing autophagy substrate clearance deficits as a basis for autophagic flux declines. The findings collectively suggest that upregulated lysosomal biogenesis and preserved proteolysis maintain autophagic clearance in early-stage HD, but failure at advanced stages contributes to progressive HTT build-up and potential neurotoxicity. These findings support the prospect that ALP stimulation applied at early disease stages, when clearance machinery is fully competent, may have therapeutic benefits in HD patients.<\/jats:p>","DOI":"10.1101\/2024.05.29.596470","type":"posted-content","created":{"date-parts":[[2024,5,31]],"date-time":"2024-05-31T02:20:15Z","timestamp":1717122015000},"source":"Crossref","is-referenced-by-count":12,"title":["Pathobiology of the autophagy-lysosomal pathway in the Huntington\u2019s disease brain"],"prefix":"10.64898","author":[{"given":"Martin J.","family":"Berg","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"family":"Veeranna","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Corrinne M.","family":"Rosa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Asok","family":"Kumar","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Panaiyur S.","family":"Mohan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Philip","family":"Stavrides","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Deanna M.","family":"Marchionini","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dun-Sheng","family":"Yang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ralph A.","family":"Nixon","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2024060120500977000_2024.05.29.596470v1.1","doi-asserted-by":"publisher","DOI":"10.1038\/nature22078"},{"key":"2024060120500977000_2024.05.29.596470v1.2","doi-asserted-by":"publisher","DOI":"10.1016\/j.chembiol.2011.12.020"},{"key":"2024060120500977000_2024.05.29.596470v1.3","doi-asserted-by":"crossref","first-page":"15005","DOI":"10.1038\/nrdp.2015.5","article-title":"Huntington disease","volume":"1","year":"2015","journal-title":"Nat Rev Dis Primers"},{"key":"2024060120500977000_2024.05.29.596470v1.4","doi-asserted-by":"publisher","DOI":"10.1111\/j.1750-3639.1998.tb00196.x"},{"key":"2024060120500977000_2024.05.29.596470v1.5","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainresbull.2011.03.013"},{"key":"2024060120500977000_2024.05.29.596470v1.6","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainresbull.2011.05.005"},{"key":"2024060120500977000_2024.05.29.596470v1.7","doi-asserted-by":"publisher","DOI":"10.1006\/nbdi.1998.0168"},{"key":"2024060120500977000_2024.05.29.596470v1.8","doi-asserted-by":"publisher","DOI":"10.1080\/15548627.2016.1239003"},{"key":"2024060120500977000_2024.05.29.596470v1.9","doi-asserted-by":"publisher","DOI":"10.1016\/0006-8993(90)90456-L"},{"key":"2024060120500977000_2024.05.29.596470v1.10","doi-asserted-by":"crossref","first-page":"686086","DOI":"10.3389\/fmolb.2021.686086","article-title":"Investigating Crosstalk Among PTMs Provides Novel Insight Into the Structural Basis Underlying the Differential Effects of Nt17 PTMs on Mutant Httex1 Aggregation","volume":"8","year":"2021","journal-title":"Front Mol Biosci"},{"key":"2024060120500977000_2024.05.29.596470v1.11","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2018.08.010"},{"key":"2024060120500977000_2024.05.29.596470v1.12","doi-asserted-by":"publisher","DOI":"10.1111\/j.1471-4159.1986.tb13054.x"},{"key":"2024060120500977000_2024.05.29.596470v1.13","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)80513-9"},{"key":"2024060120500977000_2024.05.29.596470v1.14","doi-asserted-by":"publisher","DOI":"10.1098\/rstb.1999.0449"},{"key":"2024060120500977000_2024.05.29.596470v1.15","doi-asserted-by":"publisher","DOI":"10.1126\/science.277.5334.1990"},{"issue":"2","key":"2024060120500977000_2024.05.29.596470v1.16","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1002\/mds.29703","article-title":"The Huntington\u2019s Disease Gene Discovery","volume":"39","year":"2024","journal-title":"Mov Disord"},{"key":"2024060120500977000_2024.05.29.596470v1.17","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.22-12-04842.2002"},{"key":"2024060120500977000_2024.05.29.596470v1.18","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.19-07-02522.1999"},{"issue":"5","key":"2024060120500977000_2024.05.29.596470v1.19","doi-asserted-by":"crossref","first-page":"294","DOI":"10.1093\/jnen\/nlae022","article-title":"Postmortem neuropathology in early Huntington disease","volume":"83","year":"2024","journal-title":"J Neuropathol Exp Neurol"},{"key":"2024060120500977000_2024.05.29.596470v1.20","doi-asserted-by":"publisher","DOI":"10.4161\/auto.6.8.13617"},{"issue":"1","key":"2024060120500977000_2024.05.29.596470v1.21","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1186\/s10020-024-00801-2","article-title":"Huntingtin HTT1a is generated in a CAG repeat-length-dependent manner in human tissues","volume":"30","year":"2024","journal-title":"Mol Med"},{"key":"2024060120500977000_2024.05.29.596470v1.22","first-page":"30","article-title":"Lysosomal dysfunction in Down syndrome and Alzheimer mouse models is caused by v-ATPase inhibition by Tyr(682)-phosphorylated APP betaCTF","volume":"9","year":"2023","journal-title":"Sci Adv"},{"key":"2024060120500977000_2024.05.29.596470v1.23","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2990.1995.tb01024.x"},{"key":"2024060120500977000_2024.05.29.596470v1.24","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.RA117.000435"},{"key":"2024060120500977000_2024.05.29.596470v1.25","first-page":"16","article-title":"From Pathogenesis to Therapeutics: A Review of 150 Years of Huntington\u2019s Disease Research","volume":"24","year":"2023","journal-title":"Int J Mol Sci"},{"key":"2024060120500977000_2024.05.29.596470v1.26","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.20-19-07268.2000"},{"key":"2024060120500977000_2024.05.29.596470v1.27","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.221451398"},{"key":"2024060120500977000_2024.05.29.596470v1.28","doi-asserted-by":"publisher","DOI":"10.15252\/embj.2021108863"},{"key":"2024060120500977000_2024.05.29.596470v1.29","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddy141"},{"key":"2024060120500977000_2024.05.29.596470v1.30","doi-asserted-by":"publisher","DOI":"10.1016\/S0361-9230(01)00599-8"},{"key":"2024060120500977000_2024.05.29.596470v1.31","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.3219-11.2011"},{"key":"2024060120500977000_2024.05.29.596470v1.32","doi-asserted-by":"publisher","DOI":"10.1021\/jacs.1c03108"},{"key":"2024060120500977000_2024.05.29.596470v1.33","first-page":"2","article-title":"Subcellular Localization And Formation Of Huntingtin Aggregates Correlates With Symptom Onset And Progression In A Huntington\u2019S Disease Model","volume":"2","year":"2020","journal-title":"Brain Commun"},{"key":"2024060120500977000_2024.05.29.596470v1.34","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M109.075028"},{"key":"2024060120500977000_2024.05.29.596470v1.35","doi-asserted-by":"publisher","DOI":"10.1038\/s41593-022-01084-8"},{"key":"2024060120500977000_2024.05.29.596470v1.36","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2021.109034"},{"key":"2024060120500977000_2024.05.29.596470v1.37","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2013.06.020"},{"key":"2024060120500977000_2024.05.29.596470v1.38","doi-asserted-by":"publisher","DOI":"10.1016\/S1097-2765(02)00602-0"},{"issue":"2","key":"2024060120500977000_2024.05.29.596470v1.39","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1097\/00005072-199902000-00003","article-title":"Distribution of inclusions in neuronal nuclei and dystrophic neurites in Huntington disease brain","volume":"58","year":"1999","journal-title":"J Neuropathol Exp Neurol"},{"key":"2024060120500977000_2024.05.29.596470v1.40","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)81369-0"},{"key":"2024060120500977000_2024.05.29.596470v1.41","doi-asserted-by":"publisher","DOI":"10.1016\/0022-510X(95)00035-Z"},{"key":"2024060120500977000_2024.05.29.596470v1.42","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-24411-2"},{"key":"2024060120500977000_2024.05.29.596470v1.43","doi-asserted-by":"publisher","DOI":"10.1016\/j.tins.2014.09.003"},{"key":"2024060120500977000_2024.05.29.596470v1.44","doi-asserted-by":"publisher","DOI":"10.1038\/nn.2528"},{"key":"2024060120500977000_2024.05.29.596470v1.45","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.21-06-01830.2001"},{"key":"2024060120500977000_2024.05.29.596470v1.46","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2010.06.021"},{"issue":"1","key":"2024060120500977000_2024.05.29.596470v1.47","doi-asserted-by":"crossref","first-page":"1307","DOI":"10.1038\/s41598-017-01510-z","article-title":"The pathogenic exon 1 HTT protein is produced by incomplete splicing in Huntington\u2019s disease patients","volume":"7","year":"2017","journal-title":"Sci Rep"},{"issue":"9","key":"2024060120500977000_2024.05.29.596470v1.48","doi-asserted-by":"crossref","first-page":"140443","DOI":"10.1016\/j.bbapap.2020.140443","article-title":"The aging lysosome: An essential catalyst for late-onset neurodegenerative diseases","volume":"1868","year":"2020","journal-title":"Biochim Biophys Acta Proteins Proteom"},{"key":"2024060120500977000_2024.05.29.596470v1.49","doi-asserted-by":"crossref","unstructured":"Nixon, R. A. and D. C. Rubinsztein (2024). \u201cMechanisms of Autophagy-Lysosome Dysfunction in Neurodegenerative Diseases.\u201d Nat Rev Mol Cell Biol In press.","DOI":"10.1038\/s41580-024-00757-5"},{"key":"2024060120500977000_2024.05.29.596470v1.50","doi-asserted-by":"publisher","DOI":"10.1093\/jnen\/64.2.113"},{"key":"2024060120500977000_2024.05.29.596470v1.51","doi-asserted-by":"publisher","DOI":"10.4161\/auto.6.8.13337"},{"key":"2024060120500977000_2024.05.29.596470v1.52","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1420103111"},{"key":"2024060120500977000_2024.05.29.596470v1.53","doi-asserted-by":"publisher","DOI":"10.1038\/s41593-022-01185-4"},{"key":"2024060120500977000_2024.05.29.596470v1.54","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awab473"},{"key":"2024060120500977000_2024.05.29.596470v1.55","doi-asserted-by":"crossref","unstructured":"Pressl, C. , K. M\u00e4tlik , L. Kus , P. Darnell , J. D. Luo , M. R. Paul , A. R. Weiss , W. Liguore , T. S. Carroll , D. A. Davis , J. McBride and N. Heintz (2024). \u201cSelective vulnerability of layer 5a corticostriatal neurons in Huntington\u2019s disease.\u201d Neuron.","DOI":"10.2139\/ssrn.4486500"},{"key":"2024060120500977000_2024.05.29.596470v1.56","first-page":"349","article-title":"Huntingtin promotes mTORC1 signaling in the pathogenesis of Huntington\u2019s disease","volume":"7","year":"2014","journal-title":"Sci Signal"},{"key":"2024060120500977000_2024.05.29.596470v1.57","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddg346"},{"key":"2024060120500977000_2024.05.29.596470v1.58","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/11.9.1107"},{"key":"2024060120500977000_2024.05.29.596470v1.59","doi-asserted-by":"publisher","DOI":"10.1038\/ng1362"},{"issue":"1","key":"2024060120500977000_2024.05.29.596470v1.60","doi-asserted-by":"crossref","first-page":"6579","DOI":"10.1038\/s41467-021-26684-z","article-title":"Nuclear and cytoplasmic huntingtin inclusions exhibit distinct biochemical composition, interactome and ultrastructural properties","volume":"12","year":"2021","journal-title":"Nat Commun"},{"key":"2024060120500977000_2024.05.29.596470v1.61","unstructured":"Roizin, L. S. S. ; Liu, J.C. (1979). Neuronal nuclear-cytoplasmic changes in Huntington\u2019s chorea: Electron microscope investigation. T. N. Chase . New York, Raven Press. Advances in Neurology 23: 95-122."},{"key":"2024060120500977000_2024.05.29.596470v1.62","doi-asserted-by":"publisher","DOI":"10.1097\/NEN.0b013e31816b4aee"},{"key":"2024060120500977000_2024.05.29.596470v1.63","doi-asserted-by":"publisher","DOI":"10.1038\/ncb3101"},{"key":"2024060120500977000_2024.05.29.596470v1.64","doi-asserted-by":"crossref","first-page":"895","DOI":"10.1038\/srep00895","article-title":"Cellular inclusion bodies of mutant huntingtin exon 1 obscure small fibrillar aggregate species","volume":"2","year":"2012","journal-title":"Sci Rep"},{"key":"2024060120500977000_2024.05.29.596470v1.65","doi-asserted-by":"crossref","unstructured":"Sanchez-Garrido, J. , V. Sancho-Shimizu and A. R. Shenoy (2018). \u201cRegulated proteolysis of p62\/SQSTM1 enables differential control of autophagy and nutrient sensing.\u201d Sci Signal 11(559).","DOI":"10.1126\/scisignal.aat6903"},{"key":"2024060120500977000_2024.05.29.596470v1.66","doi-asserted-by":"crossref","first-page":"485","DOI":"10.3389\/fchem.2020.00485","article-title":"Strategies to Investigate Ubiquitination in Huntington\u2019s Disease","volume":"8","year":"2020","journal-title":"Front Chem"},{"key":"2024060120500977000_2024.05.29.596470v1.67","doi-asserted-by":"publisher","DOI":"10.1002\/ana.410420411"},{"key":"2024060120500977000_2024.05.29.596470v1.68","doi-asserted-by":"publisher","DOI":"10.1111\/j.1742-4658.2008.06562.x"},{"key":"2024060120500977000_2024.05.29.596470v1.69","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1221891110"},{"issue":"5","key":"2024060120500977000_2024.05.29.596470v1.70","doi-asserted-by":"crossref","first-page":"910","DOI":"10.1016\/j.neuron.2016.02.003","article-title":"The Biology of Huntingtin","volume":"89","year":"2016","journal-title":"Neuron"},{"key":"2024060120500977000_2024.05.29.596470v1.71","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)80514-0"},{"issue":"4","key":"2024060120500977000_2024.05.29.596470v1.72","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1097\/nen.0b013e318040b2c8","article-title":"Characterization of huntingtin pathologic fragments in human Huntington disease, transgenic mice, and cell models","volume":"66","year":"2007","journal-title":"J Neuropathol Exp Neurol"},{"key":"2024060120500977000_2024.05.29.596470v1.73","doi-asserted-by":"publisher","DOI":"10.1016\/0003-2697(85)90442-7"},{"key":"2024060120500977000_2024.05.29.596470v1.74","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.41.7.1117"},{"key":"2024060120500977000_2024.05.29.596470v1.75","doi-asserted-by":"crossref","unstructured":"Stavrides, P. , C. N. Goulbourne , J. Peddy , C. Huo , M. V. Rao , V. Khetarpal , D. M. Marchionini , R. A. Nixon and D. S. Yang (2024). \u201cOral mTOR inhibition in Q175 Huntington\u2019s disease model mice ameliorates neuronal autophagy and mutant huntingtin clearance.\u201d bioRxiv.","DOI":"10.1101\/2024.05.29.596471"},{"key":"2024060120500977000_2024.05.29.596470v1.76","doi-asserted-by":"publisher","DOI":"10.1111\/j.1471-4159.2008.05385.x"},{"key":"2024060120500977000_2024.05.29.596470v1.77","doi-asserted-by":"publisher","DOI":"10.1097\/00005072-197404000-00008"},{"key":"2024060120500977000_2024.05.29.596470v1.78","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(93)90585-E"},{"key":"2024060120500977000_2024.05.29.596470v1.79","doi-asserted-by":"crossref","first-page":"106291","DOI":"10.1016\/j.nbd.2023.106291","article-title":"Aberrant splicing of mutant huntingtin in Huntington\u2019s disease knock-in pigs","volume":"187","year":"2023","journal-title":"Neurobiol Dis"},{"issue":"6","key":"2024060120500977000_2024.05.29.596470v1.80","doi-asserted-by":"crossref","first-page":"1211","DOI":"10.1038\/s41418-021-00912-x","article-title":"The caspase-6-p62 axis modulates p62 droplets based autophagy in a dominant-negative manner","volume":"29","year":"2022","journal-title":"Cell Death Differ"},{"key":"2024060120500977000_2024.05.29.596470v1.81","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-007-0306-6"},{"key":"2024060120500977000_2024.05.29.596470v1.82","doi-asserted-by":"publisher","DOI":"10.1097\/00005072-198511000-00003"},{"key":"2024060120500977000_2024.05.29.596470v1.83","doi-asserted-by":"publisher","DOI":"10.1002\/anie.201206561"},{"key":"2024060120500977000_2024.05.29.596470v1.84","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.22-18-07862.2002"},{"key":"2024060120500977000_2024.05.29.596470v1.85","doi-asserted-by":"publisher","DOI":"10.1186\/s13024-016-0141-0"},{"key":"2024060120500977000_2024.05.29.596470v1.86","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.200510065"},{"issue":"10","key":"2024060120500977000_2024.05.29.596470v1.87","doi-asserted-by":"crossref","first-page":"3256","DOI":"10.1080\/15548627.2021.1953820","article-title":"SQSTM1\/p62 droplet -mediated autophagosome formation:insights into Huntington disease","volume":"17","year":"2021","journal-title":"Autophagy"},{"key":"2024060120500977000_2024.05.29.596470v1.88","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.200505082"},{"issue":"1","key":"2024060120500977000_2024.05.29.596470v1.89","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1186\/s40478-021-01172-z","article-title":"Correlative light and electron microscopy suggests that mutant huntingtin dysregulates the endolysosomal pathway in presymptomatic Huntington\u2019s disease","volume":"9","year":"2021","journal-title":"Acta Neuropathol Commun"},{"key":"2024060120500977000_2024.05.29.596470v1.90","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M110.187591"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1101\/2024.05.29.596470","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T06:29:31Z","timestamp":1768458571000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.1101\/2024.05.29.596470"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,5,30]]},"references-count":90,"URL":"https:\/\/doi.org\/10.1101\/2024.05.29.596470","relation":{},"subject":[],"published":{"date-parts":[[2024,5,30]]},"subtype":"preprint"}}