{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,11]],"date-time":"2025-11-11T05:19:08Z","timestamp":1762838348205,"version":"build-2065373602"},"reference-count":37,"publisher":"MDPI AG","issue":"22","license":[{"start":{"date-parts":[[2025,11,8]],"date-time":"2025-11-08T00:00:00Z","timestamp":1762560000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002915","name":"Fondation pour la Recherche M\u00e9dicale","doi-asserted-by":"publisher","award":["FRM: MND202004011475"],"award-info":[{"award-number":["FRM: MND202004011475"]}],"id":[{"id":"10.13039\/501100002915","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001665","name":"Agence Nationale de la Recherche","doi-asserted-by":"crossref","award":["ANR-24-CE17-4799-01"],"award-info":[{"award-number":["ANR-24-CE17-4799-01"]}],"id":[{"id":"10.13039\/501100001665","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disorder characterized by motor neuron (MN) degeneration, frequently overlapping with frontotemporal dementia (FTD). Protein aggregation is a hallmark of these disorders, yet the role of aggregates in ALS pathogenesis remains unclear. Previously, stomatin-like protein 2 (SLP2) and prohibitin (PHB) aggregates were identified in a model of CHCHD10-related ALS (Chchd10S59L\/+ mice). This study raises the question of the presence and possible involvement of these aggregates in ALS beyond CHCHD10-associated motor neuron disease (MND). Using immunohistofluorescence, we analyzed SLP2\/PHB expression in the spinal MNs and hippocampus of two ALS mouse models: Fus\u0394NLS and Sod1G86R. Additionally, post-mortem spinal cord tissues from 27 ALS and ALS-FTD patients were analyzed. SLP2\/PHB aggregates were identified in spinal MNs and the hippocampus of Fus\u0394NLS mice but not in Sod1G86R mice. In ALS patients, SLP2\/PHB aggregation was observed in four cases, including two with C9ORF72 mutations. Interestingly, aggregates were absent in SOD1-associated ALS patients. These findings suggest that SLP2\/PHB aggregation is not specific to CHCHD10 variants but may contribute to the pathogenesis of ALS from different origins. The age-related accumulation of these aggregates highlights their potential role in disease progression and as therapeutic targets. Future studies should investigate their mechanistic contributions across different ALS subtypes.<\/jats:p>","DOI":"10.3390\/ijms262210852","type":"journal-article","created":{"date-parts":[[2025,11,10]],"date-time":"2025-11-10T08:57:55Z","timestamp":1762765075000},"page":"10852","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["SLP2\/PHB Aggregates in ALS Mouse Models and Patients: Implications Beyond CHCHD10-Associated Motor Neuron Disease"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3039-7101","authenticated-orcid":false,"given":"Emmanuelle C.","family":"Genin","sequence":"first","affiliation":[{"name":"Team \u201cMitochondria, Diseases and Aging\u201d, Institute for Research on Cancer and Aging, Nice (IRCAN), Inserm U1081, CNRS UMR7284, Universit\u00e9 C\u00f4te d\u2019Azur (UniCA), 06107 Nice, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fran\u00e7oise","family":"Lespinasse","sequence":"additional","affiliation":[{"name":"Team \u201cMitochondria, Diseases and Aging\u201d, Institute for Research on Cancer and Aging, Nice (IRCAN), Inserm U1081, CNRS UMR7284, Universit\u00e9 C\u00f4te d\u2019Azur (UniCA), 06107 Nice, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alessandra","family":"Mauri-Crouzet","sequence":"additional","affiliation":[{"name":"Team \u201cMitochondria, Diseases and Aging\u201d, Institute for Research on Cancer and Aging, Nice (IRCAN), Inserm U1081, CNRS UMR7284, Universit\u00e9 C\u00f4te d\u2019Azur (UniCA), 06107 Nice, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Luc","family":"Dupuis","sequence":"additional","affiliation":[{"name":"Centre de Recherche en Biom\u00e9decine, Strasbourg Translational Neuroscience and Psychiatry, UMR-S1329, Inserm, Universit\u00e9 de Strasbourg, 67000 Strasbourg, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"V\u00e9ronique","family":"Paquis-Flucklinger","sequence":"additional","affiliation":[{"name":"Team \u201cMitochondria, Diseases and Aging\u201d, Institute for Research on Cancer and Aging, Nice (IRCAN), Inserm U1081, CNRS UMR7284, Universit\u00e9 C\u00f4te d\u2019Azur (UniCA), 06107 Nice, France"},{"name":"Department of Medical Genetics & Reference Centre for Mitochondrial Disease, Nice Universitary Hospital, 06202 Nice, France"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,11,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1918","DOI":"10.1111\/ene.14393","article-title":"Amyotrophic Lateral Sclerosis: A Clinical Review","volume":"27","author":"Masrori","year":"2020","journal-title":"Eur. J. Neurol."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Genin, E.C., Abou-Ali, M., and Paquis-Flucklinger, V. (2023). Mitochondria, a Key Target in Amyotrophic Lateral Sclerosis Pathogenesis. Genes, 14.","DOI":"10.3390\/genes14111981"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Rizea, R.E., Corlatescu, A.-D., Costin, H.P., Dumitru, A., and Ciurea, A.V. (2024). Understanding Amyotrophic Lateral Sclerosis: Pathophysiology, Diagnosis, and Therapeutic Advances. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25189966"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Parobkova, E., and Matej, R. (2021). Amyotrophic Lateral Sclerosis and Frontotemporal Lobar Degenerations: Similarities in Genetic Background. Diagnostics, 11.","DOI":"10.3390\/diagnostics11030509"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2084","DOI":"10.1016\/S0140-6736(17)31287-4","article-title":"Amyotrophic Lateral Sclerosis","volume":"390","author":"Hardiman","year":"2017","journal-title":"Lancet"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Petrov, D., Mansfield, C., Moussy, A., and Hermine, O. (2017). ALS Clinical Trials Review: 20 Years of Failure. Are We Any Closer to Registering a New Treatment?. Front. Aging Neurosci., 9.","DOI":"10.3389\/fnagi.2017.00068"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Benson, B.C., Shaw, P.J., Azzouz, M., Highley, J.R., and Hautbergue, G.M. (2021). Proteinopathies as Hallmarks of Impaired Gene Expression, Proteostasis and Mitochondrial Function in Amyotrophic Lateral Sclerosis. Front. Neurosci., 15.","DOI":"10.3389\/fnins.2021.783624"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"693","DOI":"10.1016\/j.cell.2022.12.032","article-title":"Hallmarks of Neurodegenerative Diseases","volume":"186","author":"Wilson","year":"2023","journal-title":"Cell"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1186\/s40478-022-01386-9","article-title":"Modulation of Synaptic Plasticity, Motor Unit Physiology, and TDP-43 Pathology by CHCHD10","volume":"10","author":"Liu","year":"2022","journal-title":"Acta Neuropathol. Commun."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Genin, E.C., di Borgo, P.P., Lorivel, T., Hugues, S., Farinelli, M., Mauri-Crouzet, A., Lespinasse, F., Godin, L., Paquis-Flucklinger, V., and Petit-Paitel, A. (2024). CHCHD10S59L\/+ Mouse Model: Behavioral and Neuropathological Features of Frontotemporal Dementia. Neurobiol. Dis., 195.","DOI":"10.1016\/j.nbd.2024.106498"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1007\/s00401-019-01988-z","article-title":"Mitochondrial Defect in Muscle Precedes Neuromuscular Junction Degeneration and Motor Neuron Death in CHCHD10S59L\/+ Mouse","volume":"138","author":"Genin","year":"2019","journal-title":"Acta Neuropathol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1007\/s00401-019-01989-y","article-title":"ALS\/FTD Mutant CHCHD10 Mice Reveal a Tissue-Specific Toxic Gain-of-Function and Mitochondrial Stress Response","volume":"138","author":"Anderson","year":"2019","journal-title":"Acta Neuropathol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"e157504","DOI":"10.1172\/JCI157504","article-title":"OMA1 Mediates Local and Global Stress Responses against Protein Misfolding in CHCHD10 Mitochondrial Myopathy","volume":"132","author":"Shammas","year":"2022","journal-title":"J. Clin. Investig."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"e394","DOI":"10.1212\/NXG.0000000000000394","article-title":"Neuropathologic Description of CHCHD10 Mutated Amyotrophic Lateral Sclerosis","volume":"6","author":"Keith","year":"2020","journal-title":"Neurol. Genet."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"3415","DOI":"10.1093\/brain\/awac197","article-title":"CHCHD10 and SLP2 Control the Stability of the PHB Complex: A Key Factor for Motor Neuron Viability","volume":"145","author":"Genin","year":"2022","journal-title":"Brain"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2329","DOI":"10.1093\/brain\/awu138","article-title":"A Mitochondrial Origin for Frontotemporal Dementia and Amyotrophic Lateral Sclerosis through CHCHD10 Involvement","volume":"137","author":"Bannwarth","year":"2014","journal-title":"Brain"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"e311","DOI":"10.1093\/brain\/awu265","article-title":"Mutations in the CHCHD10 Gene Are a Common Cause of Familial Amyotrophic Lateral Sclerosis","volume":"137","author":"Johnson","year":"2014","journal-title":"Brain"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"e380","DOI":"10.1093\/brain\/awv082","article-title":"Mutation Analysis of CHCHD10 in Different Neurodegenerative Diseases","volume":"138","author":"Zhang","year":"2015","journal-title":"Brain"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2884.e1","DOI":"10.1016\/j.neurobiolaging.2014.07.022","article-title":"Screening of CHCHD10 in a French Cohort Confirms the Involvement of This Gene in Frontotemporal Dementia with Amyotrophic Lateral Sclerosis Patients","volume":"35","author":"Chaussenot","year":"2014","journal-title":"Neurobiol. Aging"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"e21","DOI":"10.1093\/brain\/awv367","article-title":"High Prevalence of CHCHD10 Mutation in Patients with Frontotemporal Dementia from China","volume":"139","author":"Jiao","year":"2016","journal-title":"Brain"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"904","DOI":"10.1016\/j.bbamcr.2008.02.006","article-title":"SLP-2 Interacts with Prohibitins in the Mitochondrial Inner Membrane and Contributes to Their Stability","volume":"1783","author":"Parone","year":"2008","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"274","DOI":"10.1006\/nbdi.2000.0292","article-title":"Differential Screening of Mutated SOD1 Transgenic Mice Reveals Early Up-Regulation of a Fast Axonal Transport Component in Spinal Cord Motor Neurons","volume":"7","author":"Dupuis","year":"2000","journal-title":"Neurobiol. Dis."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"689","DOI":"10.1073\/pnas.92.3.689","article-title":"Transgenic Mice Expressing an Altered Murine Superoxide Dismutase Gene Provide an Animal Model of Amyotrophic Lateral Sclerosis","volume":"92","author":"Ripps","year":"1995","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"887","DOI":"10.1007\/s00401-017-1687-9","article-title":"Motor Neuron Intrinsic and Extrinsic Mechanisms Contribute to the Pathogenesis of FUS-Associated Amyotrophic Lateral Sclerosis","volume":"133","author":"Oussini","year":"2017","journal-title":"Acta Neuropathol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1077","DOI":"10.15252\/embj.201592559","article-title":"Toxic Gain of Function from Mutant FUS Protein Is Crucial to Trigger Cell Autonomous Motor Neuron Loss","volume":"35","author":"Sendscheid","year":"2016","journal-title":"EMBO J."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"4147","DOI":"10.1523\/JNEUROSCI.5461-05.2006","article-title":"Overloading of Stable and Exclusion of Unstable Human Superoxide Dismutase-1 Variants in Mitochondria of Murine Amyotrophic Lateral Sclerosis Models","volume":"26","author":"Bergemalm","year":"2006","journal-title":"J. Neurosci."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"485","DOI":"10.1080\/21678421.2020.1779298","article-title":"Focus on the Heterogeneity of Amyotrophic Lateral Sclerosis","volume":"21","author":"Bendotti","year":"2020","journal-title":"Amyotroph. Lateral Scler. Front. Degener."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Tzeplaeff, L., J\u00fcrs, A.V., Wohnrade, C., and Demleitner, A.F. (2024). Unraveling the Heterogeneity of ALS\u2014A Call to Redefine Patient Stratification for Better Outcomes in Clinical Trials. Cells, 13.","DOI":"10.3390\/cells13050452"},{"key":"ref_29","first-page":"5497046","article-title":"Proteostasis Failure in Neurodegenerative Diseases: Focus on Oxidative Stress","volume":"2020","author":"Tramutola","year":"2020","journal-title":"Oxid. Med. Cell Longev."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1016\/j.tcb.2020.01.008","article-title":"Mechanisms Linking Mitochondrial Dysfunction and Proteostasis Failure","volume":"30","author":"Lu","year":"2020","journal-title":"Trends Cell Biol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"290","DOI":"10.1186\/s12964-025-02308-7","article-title":"Mitochondrial Dysfunction in the Regulation of Aging and Aging-Related Diseases","volume":"23","author":"Zhang","year":"2025","journal-title":"Cell Commun. Signal"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1016\/j.nbd.2018.07.005","article-title":"Autophagy and Mitophagy in ALS","volume":"122","author":"Evans","year":"2019","journal-title":"Neurobiol. Dis."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"254","DOI":"10.1080\/15548627.2021.1926656","article-title":"Autophagy and ALS: Mechanistic Insights and Therapeutic Implications","volume":"18","author":"Chua","year":"2022","journal-title":"Autophagy"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Madruga, E., Maestro, I., and Mart\u00ednez, A. (2021). Mitophagy Modulation, a New Player in the Race against ALS. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22020740"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"10749","DOI":"10.1007\/s11033-022-07738-x","article-title":"Role of Mitophagy in Neurodegenerative Diseases and Potential Tagarts for Therapy","volume":"49","author":"Jiao","year":"2022","journal-title":"Mol. Biol. Rep."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1186\/s13024-021-00477-w","article-title":"Wild-Type FUS Corrects ALS-like Disease Induced by Cytoplasmic Mutant FUS through Autoregulation","volume":"16","author":"Dieterle","year":"2021","journal-title":"Mol. Neurodegener."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"342","DOI":"10.1038\/s41467-022-35724-1","article-title":"Integrative Genetic Analysis Illuminates ALS Heritability and Identifies Risk Genes","volume":"14","author":"Megat","year":"2023","journal-title":"Nat. Commun."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/22\/10852\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,11]],"date-time":"2025-11-11T05:17:18Z","timestamp":1762838238000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/22\/10852"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,8]]},"references-count":37,"journal-issue":{"issue":"22","published-online":{"date-parts":[[2025,11]]}},"alternative-id":["ijms262210852"],"URL":"https:\/\/doi.org\/10.3390\/ijms262210852","relation":{},"ISSN":["1422-0067"],"issn-type":[{"type":"electronic","value":"1422-0067"}],"subject":[],"published":{"date-parts":[[2025,11,8]]}}}