Protein aggregation in progressive myoclonus epilepsies and related syndromes

Abstract

For this review paper, data on protein misfolding and aggregation in progressive myoclonus epilepsies and some developmental encephalopathies are gathered. There is evidence that in some cases of monogenic epilepsies, misfolding of the mutated protein takes place, often leading to protein aggregation. On one hand, protein aggregation reduces the amount of protein and its activity; on the other, it exerts generic toxicity to neurons. Understanding the molecular causes due to loss of normal function and gain of toxic function of the mutated aggregate-prone proteins is important to obtain new therapies. By observing the symptomatology of progressive and developmental epileptic syndromes, one can derive some conclusions about the relevance of protein misfolding and aggregation in the picture. A plausible view seems that the most severe symptoms of dementia, behavioral and psychiatric symptoms, are linked to protein aggregation and downstream effects on cellular degradation and energy systems. Finally, I discuss the potential of targeting the proteostasis network to develop novel anti-seizure and neuroprotective therapies.

Keywords

protein aggregation / neurodegeneration / epilepsy / PMEs / LD / ULD / Dravet syndrome / FENIB

References

[1] Wang J, Dai L, Zhang Z. Protein aggregation in neurodegenerative diseases. Chin Med J (Engl). 2025; 138:2753-68.

[2] Verde EM, Secco V, Ghezzi A, Mandrioli J, Carra S. Molecular Mechanisms of Protein Aggregation in ALS-FTD: Focus on TDP-43 and Cellular Protective Responses. Cells. 2025; 14:680.

[3] Dharmasri PA, Levy AD, Blanpied TA. Differential nanoscale organization of excitatory synapses onto excitatory vs. inhibitory neurons. Proc Natl Acad Sci U S A. 2024; 121:e2315379121.

[4] Waxham MN. Chapter 8 - Neurotransmitter Receptors. In: Squire LR, Berg D, Bloom FE, du Lac S, Ghosh A, Spitzer NC. editors.Fundamental Neuroscience (Fourth Edition). San Diego: Academic Press; 2013pp. 163–87.

[5] Traynelis SF, Wollmuth LP, McBain CJ, Menniti FS, Vance KM, Ogden KK, et al.Glutamate receptor ion channels: structure, regulation, and function. Pharmacol Rev. 2010; 62:405-96.

[6] Khoshnam SE, Winlow W, Farzaneh M, Farbood Y, Moghaddam HF. Pathogenic mechanisms following ischemic stroke. Neurol Sci. 2017; 38:1167-86.

[7] Dong X, Wang Y, Qin Z. Molecular mechanisms of excitotoxicity and their relevance to pathogenesis of neurodegenerative diseases. Acta Pharmacol Sin. 2009; 30:379-87.

[8] Michalska P, León R. When It Comes to an End: Oxidative Stress Crosstalk with Protein Aggregation and Neuroinflammation Induce Neurodegeneration. Antioxidants (Basel). 2020; 9:740.

[9] Daponte A, Koros C, Skarlis C, Siozios D, Rentzos M, Papageorgiou SG, et al.Neurofilament Biomarkers in Neurology: From Neuroinflammation to Neurodegeneration, Bridging Established and Novel Analytical Advances with Clinical Practice. Int J Mol Sci. 2025; 26:9739.

[10] Ma M, Jiang W, Zhou R. DAMPs and DAMP-sensing receptors in inflammation and diseases. Immunity. 2024; 57:752-71.

[11] Gao C, Jiang J, Tan Y, Chen S. Microglia in neurodegenerative diseases: mechanism and potential therapeutic targets. Signal Transduct Target Ther. 2023; 8:359.

[12] Casillas-Espinosa PM, Ali I, OʼBrien TJ. Neurodegenerative pathways as targets for acquired epilepsy therapy development. Epilepsia Open. 2020; 5:138-54.

[13] Aroor A, Nguyen P, Li Y, Das R, Lugo JN, Brewster AL. Assessment of tau phosphorylation and β-amyloid pathology in human drug-resistant epilepsy. Epilepsia Open. 2023; 8:609-22.

[14] Madhamanchi K, Madhamanchi P, Jayalakshmi S, Panigrahi M, Patil A, Phanithi PB. Endoplasmic reticulum stress and unfolded protein accumulation correlate to seizure recurrence in focal cortical dysplasia patients. Cell Stress Chaperones. 2022; 27:633-43.

[15] Mitra S, Chen B, Wang P, Chown EE, Dear M, Guisso DR, et al.Laforin targets malin to glycogen in Lafora progressive myoclonus epilepsy. Dis Model Mech. 2023; 16:dmm049802.

[16] Rao SNR, Sharma J, Maity R, Jana NR. Co-chaperone CHIP stabilizes aggregate-prone malin, a ubiquitin ligase mutated in Lafora disease. J Biol Chem. 2010; 285:1404-13.

[17] Rao SNR, Maity R, Sharma J, Dey P, Shankar SK, Satishchandra P, et al.Sequestration of chaperones and proteasome into Lafora bodies and proteasomal dysfunction induced by Lafora disease-associated mutations of malin. Hum Mol Genet. 2010; 19:4726-34.

[18] Garyali P, Siwach P, Singh PK, Puri R, Mittal S, Sengupta S, et al.The malin-laforin complex suppresses the cellular toxicity of misfolded proteins by promoting their degradation through the ubiquitin-proteasome system. Hum Mol Genet. 2009; 18:688-700.

[19] Haltia M, Kristensson K, Sourander P. Neuropathological studies in three Scandinavian cases of progressive myoclonus epilepsy. Acta Neurol Scand. 1969; 45:63-77.

[20] Koskiniemi M, Donner M, Majuri H, Haltia M, Norio R. Progressive myoclonus epilepsy. A clinical and histopathological study. Acta Neurol Scand. 1974; 50:307-32.

[21] Cohen NR, Hammans SR, Macpherson J, Nicoll JAR. New neuropathological findings in Unverricht-Lundborg disease: neuronal intranuclear and cytoplasmic inclusions. Acta Neuropathol. 2011; 121:421-7.

[22] Joensuu T, Lehesjoki A, Kopra O. Molecular background of EPM1-Unverricht-Lundborg disease. Epilepsia. 2008; 49:557-63.

[23] Koskenkorva P, Hyppönen J, Aikiä M, Mervaala E, Kiviranta T, Eriksson K, et al.Severer phenotype in Unverricht-Lundborg disease (EPM1) patients compound heterozygous for the dodecamer repeat expansion and the c.202C>T mutation in the CSTB gene. Neurodegener Dis. 2011; 8:515-22.

[24] Rabzelj S, Turk V, Zerovnik E. In vitro study of stability and amyloid-fibril formation of two mutants of human stefin B (cystatin B) occurring in patients with EPM1. Protein Sci. 2005; 14:2713-22.

[25] Ceru S, Rabzelj S, Kopitar-Jerala N, Turk V, Zerovnik E. Protein aggregation as a possible cause for pathology in a subset of familial Unverricht-Lundborg disease. Med Hypotheses. 2005; 64:955-9.

[26] Polajnar M, Zavašnik-Bergant T, Kopitar-Jerala N, Tušek-Žnidarič M, Zerovnik E. Gain in toxic function of stefin B EPM1 mutants aggregates: correlation between cell death, aggregate number/size and oxidative stress. Biochim Biophys Acta. 2014; 1843:2089-99.

[27] Polajnar M, Ceru S, Kopitar-Jerala N, Zerovnik E. Human stefin B normal and patho-physiological role: molecular and cellular aspects of amyloid-type aggregation of certain EPM1 mutants. Front Mol Neurosci. 2012; 5:88.

[28] Ceru S, Layfield R, Zavasnik-Bergant T, Repnik U, Kopitar-Jerala N, Turk V, et al.Intracellular aggregation of human stefin B: confocal and electron microscopy study. Biol Cell. 2010; 102:319-34.

[29] Polajnar M, Zavašnik-Bergant T, Škerget K, Vizovišek M, Vidmar R, Fonović M, et al.Human stefin B role in cell's response to misfolded proteins and autophagy. PLoS One. 2014; 9:e102500.

[30] Skerget K, Taler-Vercic A, Bavdek A, Hodnik V, Ceru S, Tusek-Znidaric M, et al.Interaction between oligomers of stefin B and amyloid-beta in vitro and in cells. J Biol Chem. 2010; 285:3201-10.

[31] Taler-Verčič A, Zerovnik E. Binding of amyloid peptides to domain-swapped dimers of other amyloid-forming proteins may prevent their neurotoxicity. Bioessays. 2010; 32:1020-4.

[32] Di Giaimo R, Riccio M, Santi S, Galeotti C, Ambrosetti DC, Melli M. New insights into the molecular basis of progressive myoclonus epilepsy: a multiprotein complex with cystatin B. Hum Mol Genet. 2002; 11:2941-50.

[33] Di Giaimo R, Penna E, Pizzella A, Cirillo R, Perrone-Capano C, Crispino M. Cross Talk at the Cytoskeleton-Plasma Membrane Interface: Impact on Neuronal Morphology and Functions. Int J Mol Sci. 2020; 21:9133.

[34] Rispoli A, Cipollini E, Catania S, Di Giaimo R, Pulice G, van Houte S, et al.Insights in progressive myoclonus epilepsy: HSP70 promotes cystatin B polymerization. Biochim Biophys Acta. 2013; 1834:2591-9.

[35] Zerovnik E, Skerget K, Tusek-Znidaric M, Loeschner C, Brazier MW, Brown DR. High affinity copper binding by stefin B (cystatin B) and its role in the inhibition of amyloid fibrillation. FEBS J. 2006; 273:4250-63.

[36] Orsini A, Valetto A, Bertini V, Esposito M, Carli N, Minassian BA, et al.The best evidence for progressive myoclonic epilepsy: A pathway to precision therapy. Seizure. 2019; 71:247-57.

[37] Lomas DA, Finch JT, Seyama K, Nukiwa T, Carrell RW. Alpha 1-antitrypsin Siiyama (Ser53–>Phe). Further evidence for intracellular loop-sheet polymerization. J Biol Chem. 1993; 268:15333-5.

[38] Elliott PR, Lomas DA, Carrell RW, Abrahams JP. Inhibitory conformation of the reactive loop of alpha 1-antitrypsin. Nat Struct Biol. 1996; 3:676-81.

[39] Belorgey D, Crowther DC, Mahadeva R, Lomas DA. Mutant Neuroserpin (S49P) that causes familial encephalopathy with neuroserpin inclusion bodies is a poor proteinase inhibitor and readily forms polymers in vitro. J Biol Chem. 2002; 277:17367-73.

[40] West J, Satapathy S, Whiten DR, Kelly M, Geraghty NJ, Proctor E, et al.Neuroserpin and transthyretin are extracellular chaperones that preferentially inhibit amyloid formation. Sci Adv. 2021; 7:eabf7606.

[41] Roussel BD, Lomas DA, Crowther DC. Progressive myoclonus epilepsy associated with neuroserpin inclusion bodies (neuroserpinosis). Epileptic Disord. 2016; 18:103-10.

[42] Belorgey D, Sharp LK, Crowther DC, Onda M, Johansson J, Lomas DA. Neuroserpin Portland (Ser52Arg) is trapped as an inactive intermediate that rapidly forms polymers: implications for the epilepsy seen in the dementia FENIB. Eur J Biochem. 2004; 271:3360-7.

[43] Davis RL, Shrimpton AE, Holohan PD, Bradshaw C, Feiglin D, Collins GH, et al.Familial dementia caused by polymerization of mutant neuroserpin. Nature. 1999; 401:376-9.

[44] Hagen MC, Murrell JR, Delisle M, Andermann E, Andermann F, Guiot MC, et al.Encephalopathy with neuroserpin inclusion bodies presenting as progressive myoclonus epilepsy and associated with a novel mutation in the Proteinase Inhibitor 12 gene. Brain Pathol. 2011; 21:575-82.

[45] Kang J, Shen W, Lee M, Gallagher MJ, Macdonald RL. Slow degradation and aggregation in vitro of mutant GABAA receptor gamma2(Q351X) subunits associated with epilepsy. J Neurosci. 2010; 30:13895-905.

[46] Kang J, Shen W, Zhou C, Xu D, Macdonald RL. The human epilepsy mutation GABRG2(Q390X) causes chronic subunit accumulation and neurodegeneration. Nat Neurosci. 2015; 18:988-96.

[47] Kang J. Epileptic Mechanisms Shared by Alzheimerʼs Disease: Viewed via the Unique Lens of Genetic Epilepsy. Int J Mol Sci. 2021; 22:7133.

[48] Öztürk MM, Emgård J, García-Revilla J, Fernández-Calle R, Yang Y, Deierborg T, et al.The role of microglia in the prion-like transmission of protein aggregates in neurodegeneration. Brain Commun. 2025; 7:fcaf087.

[49] Glass CK, Saijo K, Winner B, Marchetto MC, Gage FH. Mechanisms underlying inflammation in neurodegeneration. Cell. 2010; 140:918-34.

[50] Bolós M, Llorens-Martín M, Jurado-Arjona J, Hernández F, Rábano A, Avila J. Direct Evidence of Internalization of Tau by Microglia In Vitro and In Vivo. J Alzheimers Dis. 2016; 50:77-87.

[51] Jiang T, Zhang Y, Gao Q, Zhou J, Zhu X, Lu H, et al.TREM1 facilitates microglial phagocytosis of amyloid beta. Acta Neuropathol. 2016; 132:667-83.

[52] Song N, Chen L, Xie J. Alpha-Synuclein Handling by Microglia: Activating, Combating, and Worsening. Neurosci Bull. 2021; 37:751-3.

[53] Svahn AJ, Don EK, Badrock AP, Cole NJ, Graeber MB, Yerbury JJ, et al.Nucleo-cytoplasmic transport of TDP-43 studied in real time: impaired microglia function leads to axonal spreading of TDP-43 in degenerating motor neurons. Acta Neuropathol. 2018; 136:445-59.

[54] Kourie JI, Henry CL. Ion channel formation and membrane-linked pathologies of misfolded hydrophobic proteins: the role of dangerous unchaperoned molecules. Clin Exp Pharmacol Physiol. 2002; 29:741-53.

[55] Stefani M, Dobson CM. Protein aggregation and aggregate toxicity: new insights into protein folding, misfolding diseases and biological evolution. J Mol Med (Berl). 2003; 81:678-99.

[56] Scannevin RH. Therapeutic strategies for targeting neurodegenerative protein misfolding disorders. Curr Opin Chem Biol. 2018; 44:66-74.

[57] Wu W, Gong X, Qin Z, Wang Y. Molecular mechanisms of excitotoxicity and their relevance to the pathogenesis of neurodegenerative diseases-an update. Acta Pharmacol Sin. 2025; 46:3129-42.

[58] Benatar M, Wuu J, Andersen PM, Atassi N, David W, Cudkowicz M, et al.Randomized, double-blind, placebo-controlled trial of arimoclomol in rapidly progressive SOD1 ALS. Neurology. 2018; 90:e565-74.

[59] Kirkegaard T, Gray J, Priestman DA, Wallom K, Atkins J, Olsen OD, et al.Heat shock protein-based therapy as a potential candidate for treating the sphingolipidoses. Sci Transl Med. 2016; 8:355ra118.

[60] Westerheide SD, Bosman JD, Mbadugha BNA, Kawahara TLA, Matsumoto G, Kim S, et al.Celastrols as inducers of the heat shock response and cytoprotection. J Biol Chem. 2004; 279:56053-60.

[61] Bagatell R, Whitesell L. Altered Hsp90 function in cancer: a unique therapeutic opportunity. Mol Cancer Ther. 2004; 3:1021-30.

[62] Neef DW, Jaeger AM, Thiele DJ. Heat shock transcription factor 1 as a therapeutic target in neurodegenerative diseases. Nat Rev Drug Discov. 2011; 10:930-44.

[63] Lee DJW, Kuerec AH, Maier AB. Targeting ageing with rapamycin and its derivatives in humans: a systematic review. Lancet Healthy Longev. 2024; 5:e152-62.

[64] Sarkar S, Davies JE, Huang Z, Tunnacliffe A, Rubinsztein DC. Trehalose, a novel mTOR-independent autophagy enhancer, accelerates the clearance of mutant huntingtin and alpha-synuclein. J Biol Chem. 2007; 282:5641-52.

[65] Madeo F, Eisenberg T, Pietrocola F, Kroemer G. Spermidine in health and disease. Science. 2018; 359:eaan2788.

[66] Wu Y, Li X, Zhu JX, Xie W, Le W, Fan Z, et al.Resveratrol-activated AMPK/SIRT1/autophagy in cellular models of Parkinsonʼs disease. Neurosignals. 2011; 19:163-74.

[67] Darvesh AS, Carroll RT, Bishayee A, Novotny NA, Geldenhuys WJ, Van der Schyf CJ. Curcumin and neurodegenerative diseases: a perspective. Expert Opin Investig Drugs. 2012; 21:1123-40.

[68] Lee B, Lee MJ, Park S, Oh D, Elsasser S, Chen P, et al.Enhancement of proteasome activity by a small-molecule inhibitor of USP14. Nature. 2010; 467:179-84.

[69] Chondrogianni N, Sakellari M, Lefaki M, Papaevgeniou N, Gonos ES. Proteasome activation delays aging in vitro and in vivo. Free Radic Biol Med. 2014; 71:303-20.

[70] Sena PP, Friedrich L, Villarreal A, Fath F, Sopco L, Hernández-Guillamon M, et al.Proteostasis disruption and lipid dyshomeostasis in neurodegeneration: exploring common druggable targets across sporadic and monogenic disorders. Front Mol Neurosci. 2025; 18:1681079.

[71] Cui Y, Jiang X, Feng J. The therapeutic potential of triptolide and celastrol in neurological diseases. Front Pharmacol. 2022; 13:1024955.

[72] Wong M. Rapamycin for treatment of epilepsy: antiseizure, antiepileptogenic, both, or neither?. Epilepsy Curr. 2011; 11:66-8.

[73] Huang X, Zhang H, Yang J, Wu J, McMahon J, Lin Y, et al.Pharmacological inhibition of the mammalian target of rapamycin pathway suppresses acquired epilepsy. Neurobiol Dis. 2010; 40:193-9.