{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,10]],"date-time":"2026-01-10T21:05:06Z","timestamp":1768079106497,"version":"3.49.0"},"reference-count":50,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2021,4,29]],"date-time":"2021-04-29T00:00:00Z","timestamp":1619654400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Brain Sciences"],"abstract":"<jats:p>Hereditary spastic paraplegia (HSP) and primary lateral sclerosis (PLS) are rare motor neuron diseases, which affect mostly the upper motor neurons (UMNs) in patients. The UMNs display early vulnerability and progressive degeneration, while other cortical neurons mostly remain functional. Identification of numerous mutations either directly linked or associated with HSP and PLS begins to reveal the genetic component of UMN diseases. Since each of these mutations are identified on genes that code for a protein, and because cellular functions mostly depend on protein-protein interactions, we hypothesized that the mutations detected in patients and the alterations in protein interaction domains would hold the key to unravel the underlying causes of their vulnerability. In an effort to bring a mechanistic insight, we utilized computational analyses to identify interaction partners of proteins and developed the protein-protein interaction landscape with respect to HSP and PLS. Protein-protein interaction domains, upstream regulators and canonical pathways begin to highlight key cellular events. Here we report that proteins involved in maintaining lipid homeostasis and cytoarchitectural dynamics and their interactions are of great importance for UMN health and stability. Their perturbation may result in neuronal vulnerability, and thus maintaining their balance could offer therapeutic interventions.<\/jats:p>","DOI":"10.3390\/brainsci11050578","type":"journal-article","created":{"date-parts":[[2021,4,30]],"date-time":"2021-04-30T05:10:55Z","timestamp":1619759455000},"page":"578","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Mutations and Protein Interaction Landscape Reveal Key Cellular Events Perturbed in Upper Motor Neurons with HSP and PLS"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7594-2447","authenticated-orcid":false,"given":"Oge","family":"Gozutok","sequence":"first","affiliation":[{"name":"Department of Neurology, Feinberg School of Medicine, Northwestern University, 303 E. Chicago Ave, Chicago, IL 60611, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Benjamin Ryan","family":"Helmold","sequence":"additional","affiliation":[{"name":"Department of Neurology, Feinberg School of Medicine, Northwestern University, 303 E. Chicago Ave, Chicago, IL 60611, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4125-6013","authenticated-orcid":false,"given":"P. Hande","family":"Ozdinler","sequence":"additional","affiliation":[{"name":"Department of Neurology, Feinberg School of Medicine, Northwestern University, 303 E. Chicago Ave, Chicago, IL 60611, USA"},{"name":"Center for Molecular Innovation and Drug Discovery, Center for Developmental Therapeutics, Chemistry of Life Processes Institute, Northwestern University, Evanston, IL 60611, USA"},{"name":"Mesulam Center for Cognitive Neurology and Alzheimer\u2019s Disease, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA"},{"name":"Feinberg School of Medicine, Les Turner ALS Center at Northwestern University, Chicago, IL 60611, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,4,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1146\/annurev.neuro.31.060407.125547","article-title":"Descending Pathways in Motor Control","volume":"31","author":"Lemon","year":"2008","journal-title":"Annu. Rev. Neurosci."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"16","DOI":"10.3389\/fnana.2014.00016","article-title":"Retrograde labeling, transduction, and genetic targeting allow cellular analysis of corticospinal motor neurons: Implications in health and disease","volume":"8","author":"Jara","year":"2014","journal-title":"Front. Neuroanat."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Adina Michael-Titus, P.R., and Shortland, P. (2010). Motor systems I: Descending pathways and cerebellum. The Nervous System, Churcill Livingstone. [2nd ed.].","DOI":"10.1016\/B978-0-7020-3373-5.00010-1"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"651","DOI":"10.1038\/nrneurol.2016.140","article-title":"Pathophysiological and diagnostic implications of cortical dysfunction in ALS","volume":"12","author":"Geevasinga","year":"2016","journal-title":"Nat. Rev. Neurol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"573","DOI":"10.3389\/fnins.2020.00573","article-title":"Exciting Complexity: The Role of Motor Circuit Elements in ALS Pathophysiology","volume":"14","author":"Gunes","year":"2020","journal-title":"Front. Neurosci."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"363","DOI":"10.3389\/fnins.2020.00363","article-title":"Cortical Circuit Dysfunction as a Potential Driver of Amyotrophic Lateral Sclerosis","volume":"14","author":"Brunet","year":"2020","journal-title":"Front. Neurosci."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1007\/s00401-013-1115-8","article-title":"Hereditary spastic paraplegia: Clinicopathologic features and emerging molecular mechanisms","volume":"126","author":"Fink","year":"2013","journal-title":"Acta Neuropathol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1016\/j.conb.2018.04.025","article-title":"Converging cellular themes for the hereditary spastic paraplegias","volume":"51","author":"Blackstone","year":"2018","journal-title":"Curr. Opin. Neurobiol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"204","DOI":"10.1111\/ane.12713","article-title":"The concept and diagnostic criteria of primary lateral sclerosis","volume":"136","author":"Wais","year":"2017","journal-title":"Acta Neurol. Scand."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1819","DOI":"10.1007\/s00415-018-8917-5","article-title":"Primary lateral sclerosis and the amyotrophic lateral sclerosis\u2013frontotemporal dementia spectrum","volume":"265","author":"Agarwal","year":"2018","journal-title":"J. Neurol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1080\/21678421.2020.1837175","article-title":"Better understanding the neurobiology of primary lateral sclerosis","volume":"21","author":"Ozdinler","year":"2020","journal-title":"Amyotroph. Lateral Scler. Front. Degener."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1097\/CND.0000000000000051","article-title":"Disease Burden in Upper Motor Neuron Syndromes: A survey of patient perspectives","volume":"16","author":"Andrews","year":"2014","journal-title":"J. Clin. Neuromuscul. Dis."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1016\/S0079-6123(03)43026-4","article-title":"Direct and indirect pathways for corticospinal control of upper limb motoneurons in the primate","volume":"143","author":"Lemon","year":"2004","journal-title":"Prog. Brain Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1016\/j.neuron.2011.06.031","article-title":"Selective Neuronal Vulnerability in Neurodegenerative Diseases: From Stressor Thresholds to Degeneration","volume":"71","author":"Saxena","year":"2011","journal-title":"Neuron"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"14732","DOI":"10.1038\/s41598-018-32902-4","article-title":"Protein-protein interactions reveal key canonical pathways, upstream regulators, interactome domains, and novel targets in ALS","volume":"8","author":"Dervishi","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1639","DOI":"10.1101\/gr.092759.109","article-title":"Circos: An information aesthetic for comparative genomics","volume":"19","author":"Krzywinski","year":"2009","journal-title":"Genome Res."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Genc, B., Gozutok, O., and Ozdinler, P.H. (2019). Complexity of Generating Mouse Models to Study the Upper Motor Neurons: Let Us Shift Focus from Mice to Neurons. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20163848"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"9595","DOI":"10.1073\/pnas.0510197103","article-title":"Als2-deficient mice exhibit disturbances in endosome trafficking associated with motor behavioral abnormalities","volume":"103","author":"Devon","year":"2006","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"e535","DOI":"10.1038\/cddis.2013.64","article-title":"Motor neuron degeneration in a mouse model of seipinopathy","volume":"4","author":"Guo","year":"2013","journal-title":"Cell Death Dis."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"851","DOI":"10.1007\/s12192-010-0194-x","article-title":"Inactivation of the hereditary spastic paraplegia-associated Hspd1 gene encoding the Hsp60 chaperone results in early embryonic lethality in mice","volume":"15","author":"Christensen","year":"2010","journal-title":"Cell Stress Chaperones"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1009","DOI":"10.1002\/glia.21172","article-title":"Central nervous system dysfunction in a mouse model of Fa2h deficiency","volume":"59","author":"Potter","year":"2011","journal-title":"Glia"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1173","DOI":"10.1085\/jgp.201912457","article-title":"KCNMA1-linked channelopathy","volume":"151","author":"Bailey","year":"2019","journal-title":"J. Gen. Physiol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"18997","DOI":"10.1073\/pnas.1205573109","article-title":"Genetic activation of BK currents in vivo generates bidirectional effects on neuronal excitability","volume":"109","author":"Montgomery","year":"2012","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"220","DOI":"10.1038\/s41431-017-0073-3","article-title":"De novo BK channel variant causes epilepsy by affecting voltage gating but not Ca2+ sensitivity","volume":"26","author":"Li","year":"2018","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2937","DOI":"10.1093\/hmg\/ddz117","article-title":"De novo loss-of-function KCNMA1 variants are associated with a new multiple malformation syndrome and a broad spectrum of developmental and neurological phenotypes","volume":"28","author":"Liang","year":"2019","journal-title":"Hum. Mol. Genet."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"617","DOI":"10.1146\/annurev.pharmtox.40.1.617","article-title":"14-3-3 Proteins: Structure, Function, and Regulation","volume":"40","author":"Fu","year":"2000","journal-title":"Annu. Rev. Pharmacol. Toxicol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1187","DOI":"10.3389\/fimmu.2017.01187","article-title":"TRIM25 in the Regulation of the Antiviral Innate Immunity","volume":"8","author":"Medrano","year":"2017","journal-title":"Front. Immunol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"869","DOI":"10.1083\/jcb.201312042","article-title":"ER-associated degradation: Protein quality control and beyond","volume":"204","author":"Ruggiano","year":"2014","journal-title":"J. Cell Biol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2501","DOI":"10.1159\/000452517","article-title":"FBXO6-Mediated Ubiquitination and Degradation of Ero1L Inhibits Endoplasmic Reticulum Stress-Induced Apoptosis","volume":"39","author":"Chen","year":"2016","journal-title":"Cell. Physiol. Biochem."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"43877","DOI":"10.1074\/jbc.M304157200","article-title":"Fbs2 Is a New Member of the E3 Ubiquitin Ligase Family That Recognizes Sugar Chains","volume":"278","author":"Yoshida","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"12717","DOI":"10.1074\/jbc.M709508200","article-title":"Diversity in Tissue Expression, Substrate Binding, and SCF Complex Formation for a Lectin Family of Ubiquitin Ligases","volume":"283","author":"Glenn","year":"2008","journal-title":"J. Biol. Chem."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"4764","DOI":"10.1038\/s41598-018-23284-8","article-title":"Dissection of the Role of VIMP in Endoplasmic Reticulum-Associated Degradation of CFTR\u0394F508","volume":"8","author":"Hou","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"28175","DOI":"10.1074\/jbc.M115.656660","article-title":"The VCP\/p97 and YOD1 Proteins Have Different Substrate-dependent Activities in Endoplasmic Reticulum-associated Degradation (ERAD)","volume":"290","author":"Sasset","year":"2015","journal-title":"J. Biol. Chem."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Gunay, A., Shin, H.H., Gozutok, O., Gautam, M., and Ozdinler, P.H. (2020). Importance of lipids for upper motor neuron health and disease. Semin. Cell Dev. Biol.","DOI":"10.1016\/j.semcdb.2020.11.004"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"202","DOI":"10.1159\/000258724","article-title":"Neuroimmunomodulation in the Pathogenesis of Alzheimer\u2019s Disease","volume":"17","author":"Morales","year":"2010","journal-title":"Neuroimmunomodulation"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"401","DOI":"10.3934\/Neuroscience.2020025","article-title":"Neuroimmunomodulation by estrogen in health and disease","volume":"7","author":"Priyanka","year":"2020","journal-title":"AIMS Neurosci."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"76","DOI":"10.3923\/ijp.2015.76.94","article-title":"Neuroimmunomodulation Countering Various Diseases, Disorders, Infections, Stress and Aging","volume":"11","author":"Dhama","year":"2015","journal-title":"Int. J. Pharmacol."},{"key":"ref_38","first-page":"169","article-title":"Neuroimmunomodulation and Aging","volume":"1","author":"Gemma","year":"2010","journal-title":"Aging Dis."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"300","DOI":"10.1016\/j.it.2020.02.002","article-title":"Neuroimmune Connections in Aging and Neurodegenerative Diseases","volume":"41","author":"Scheiblich","year":"2020","journal-title":"Trends Immunol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1016\/S0167-5699(99)01577-7","article-title":"Mindful immunology: Neuroimmunomodulation","volume":"21","author":"Chambers","year":"2000","journal-title":"Immunol. Today"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"196","DOI":"10.1186\/s12974-019-1589-y","article-title":"MCP1-CCR2 and neuroinflammation in the ALS motor cortex with TDP-43 pathology","volume":"16","author":"Jara","year":"2019","journal-title":"J. Neuroinflamm."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1186\/s12974-017-0896-4","article-title":"Evidence for an early innate immune response in the motor cortex of ALS","volume":"14","author":"Jara","year":"2017","journal-title":"J. Neuroinflamm."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1016\/S0896-6273(00)00124-0","article-title":"Axonal Transport of Amyloid Precursor Protein Is Mediated by Direct Binding to the Kinesin Light Chain Subunit of Kinesin-I","volume":"28","author":"Kamal","year":"2000","journal-title":"Neuron"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"643","DOI":"10.1038\/414643a","article-title":"Kinesin-mediated axonal transport of a membrane compartment containing \u03b2-secretase and presenilin-1 requires APP","volume":"414","author":"Kamal","year":"2001","journal-title":"Nature"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1313","DOI":"10.1016\/j.cub.2007.06.062","article-title":"Control of a Kinesin-Cargo Linkage Mechanism by JNK Pathway Kinases","volume":"17","author":"Horiuchi","year":"2007","journal-title":"Curr. Biol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"2386","DOI":"10.1523\/JNEUROSCI.3089-04.2005","article-title":"Axonal Transport, Amyloid Precursor Protein, Kinesin-1, and the Processing Apparatus: Revisited","volume":"25","author":"Lazarov","year":"2005","journal-title":"J. Neurosci."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"570","DOI":"10.1111\/neup.12694","article-title":"Praja1 RING-finger E3 ubiquitin ligase suppresses neuronal cytoplasmic TDP-43 aggregate formation","volume":"40","author":"Watabe","year":"2020","journal-title":"Neuropathology"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"103","DOI":"10.3389\/fncel.2019.00103","article-title":"Mitochondrial Dysfunction in Huntington\u2019s Disease; Interplay between HSF1, p53 and PGC-1\u03b1 Transcription Factors","volume":"13","author":"Intihar","year":"2019","journal-title":"Front. Cell. Neurosci."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"15095","DOI":"10.1074\/jbc.RA119.008491","article-title":"Angiogenin activates the astrocytic Nrf2\/antioxidant-response element pathway and thereby protects murine neurons from oxidative stress","volume":"294","author":"Hoang","year":"2019","journal-title":"J. Biol. Chem."},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Zhang, Z., Xu, L., and Xu, X. (2020). The role of transcription factor 7-like 2 in metabolic disorders. Obes. Rev.","DOI":"10.1111\/obr.13166"}],"container-title":["Brain Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-3425\/11\/5\/578\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T05:55:41Z","timestamp":1760162141000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-3425\/11\/5\/578"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,4,29]]},"references-count":50,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2021,5]]}},"alternative-id":["brainsci11050578"],"URL":"https:\/\/doi.org\/10.3390\/brainsci11050578","relation":{},"ISSN":["2076-3425"],"issn-type":[{"value":"2076-3425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,4,29]]}}}