Neuroscience
Mitochondrial dysfunctions in neurodegeneration
Mitochondria are multifaceted organelles central for various cellular processes that include ATP production, intracellular calcium signaling, generation of reactive oxygen species, regulation of metabolism and apoptosis. Neurons critically depend on mitochondrial function to establish membrane excitability and to execute the complex processes of neurotransmission and plasticity. Due to their complex cyto-architecture, neurons face a great challenge in maintaining and distributing mitochondria throughout their arbors for the entire duration of their lives. Maintenance of a healthy mitochondrial population implies efficient protein quality control, fusion and fission events, long and short range movements and the clearance of damaged proteins and organelles.
Research activity
The focus of our research is to understand how disturbances in each of these processes are implicated in the pathogenesis of neurodegenerative disorders. Our studies involve both inherited neurodegenerative conditions, which are primarily mitochondrial, as well as neurodegenerative diseases whose pathogenesis is secondarily associated to mitochondrial deregulation. To this end we combine integrated approaches of molecular biology and neurobiology, which rely on already available mouse models and patient samples.
Longo F, De Ritis D, Miluzio A, Fraticelli D, Baets J, Scarlato M, Santorelli FM, Biffo S, Maltecca F. Assessment of Sacsin Turnover in Patients With ARSACS: Implications for Molecular Diagnosis and Pathogenesis. Neurology. 2021 Dec 7;97(23):e2315-e2327. doi: 10.1212/WNL.0000000000012962. Epub 2021 Oct 14.PMID: 34649874
Sferruzza G, Del Bondio A, Citterio A, Vezzulli P, Guerrieri S, Radaelli M, Martinelli Boneschi F, Filippi M, Maltecca F, Bassi MT, Scarlato M.U-Fiber Leukoencephalopathy Due to a Novel Mutation in the TACO1 Gene. Neurol Genet. 2021 Mar 9;7(2):e573. doi: 10.1212/NXG.0000000000000573. eCollection 2021 Apr. PMID: 33709035
Baderna V, Schultz J, Kearns LS, Fahey M, Thompson BA, Ruddle JB, Huq A, Maltecca F. A novel AFG3L2 mutation close to AAA domain leads to aberrant OMA1 and OPA1 processing in a family with optic atrophy. Acta Neuropathol Commun. 2020 Jun 29;8(1):93. doi: 10.1186/s40478-020-00975-w. PMID: 32600459
F. Longo, S. Benedetti, A. Zambon, M. G. Natali Sora, C Di Resta, A Quattrini, F. Maltecca*, M. Ferrari and S.C. Previtali. (*corresponding author). Impaired turnover of hyperfused mitochondria in severe axonal neuropathy due to a novel DRP1 mutation. Hum Mol Genet. 2019 Sep 7. pii: ddz211. doi: 10.1093/hmg/ddz211.
Tulli S, Del Bondio A, Baderna V, Mazza D, Codazzi F, Pierson TM, Ambrosi A, Nolte D, Goizet C, Toro C, Baets J, Deconinck T, DeJonghe P, Mandich P, Casari G and Maltecca F. Pathogenic variants in the AFG3L2 proteolytic domain cause SCA28 through haploinsufficiency and proteostatic stress-driven OMA1 activation. J Med Genet. 2019 Aug;56(8):499-511. doi: 10.1136/jmedgenet-2018-105766.
Consolato F*, Maltecca F*, Tulli S, Sambri I, Casari G. (*co-first author). m-AAA and i-AAA complexes coordinate to regulate OMA1, the stress-activated supervisor of mitochondrial dynamics. J Cell Sci. 2018 Apr 9;131(7). doi: 10.1242/jcs.213546.
Duncan EJ, Larivière R, Bradshaw TY, Longo F, Sgarioto N, Hayes MJ, Romano LEL, Nethisinghe S, Giunti P, Bruntraeger MB, Durham HD, Brais B, Maltecca F, Gentil BJ, Chapple JP. Altered organization of the intermediate filament cytoskeleton and relocalization of proteostasis modulators in cells lacking the ataxia protein sacsin. Hum Mol Genet. 2017 Aug 15;26(16):3130-3143.
Maltecca F, Baseggio E, Consolato F, Mazza D, Podini P, Young SM Jr, Drago I, Bahr BA, Puliti A, Codazzi F, Quattrini A, Casari G. Purkinje neuron Ca2+ influx reduction rescues ataxia in SCA28 model. J Clin Invest. 2015 Jan;125(1):263-74. doi: 10.1172/JCI74770.
Magnoni R, Palmfeldt J, Christensen JH, Sand M, Maltecca F, Corydon TJ, West M, Casari G, Bross P. Late onset motoneuron disorder caused by mitochondrial Hsp60 chaperone deficiency in mice. Neurobiol Dis. 2013 Jun;54:12-23. doi: 10.1016/j.nbd.2013.02.012.
Maltecca F, De Stefani D, Cassina L, Consolato F, Wasilewski M, Scorrano L, Rizzuto R, Casari G. Respiratory dysfunction by AFG3L2 deficiency causes decreased mitochondrial calcium uptake via organellar network fragmentation. Hum Mol Genet. 2012 Sep 1;21(17):3858-70. doi: 10.1093/hmg/dds214.
Maltecca F, Magnoni R, Cerri F, Cox GA, Quattrini A, Casari G. Haploinsufficiency of AFG3L2, the gene responsible for spinocerebellar ataxia type 28, causes mitochondria-mediated Purkinje cell dark degeneration. J Neurosci. 2009 Jul 22;29(29):9244-54. doi: 10.1523/JNEUROSCI.1532-09.2009.
Maltecca F, Aghaie A, Schroeder DG, Cassina L, Taylor BA, Phillips SJ, Malaguti M, Previtali S, Guénet JL, Quattrini A, Cox GA, Casari G. The mitochondrial protease AFG3L2 is essential for axonal development. J Neurosci. 2008 Mar 12;28(11):2827-36. doi: 10.1523/JNEUROSCI.4677-07.2008.
Maltecca F, Filla A, Castaldo I, Coppola G, Fragassi NA, Bruni A, Cocozza S, Casari G, Servadio A & De Michele G. Intergenerational instability and marked anticipation in SCA17. Neurology 2003; 61(10):1441- 3.
