Hereditary spastic paraparesis and Motor neuron diseases with early onset

Description

Hereditary spastic paraplegia (HSP) is a genetically and clinically heterogeneous group of neurodegenerative diseases characterized by progressive spastic weakness of the lower limbs due to axonal degeneration of the corticospinal tract. Patients with “pure” HSP have isolated pyramidal signs, such as brisk reflexes, Babinski sign, spasticity, and motor deficit, which can be associated with sphincter disturbances and deep sensory loss . Complex forms may show variable combinations of optic neuropathy, retinopathy, extra pyramidal disturbance, dementia, ataxia, ichthyosis, mental retardation, deafness, and epilepsy in addition to spasticity.

In the last ten years, this group has collected a large series of HSP patients including a significant number of families with phenotypes partly overlapping with HSP such as juvenile ALS, inherited forms of cerebral palsies, recessive ataxias and complex hereditary motor neuropathy forms with early onset. Genetic analysis has then led to the identification of a large number of mutated cases in different SPG subtypes (see list of selected publications), in forms of juvenile ALS linked to ALS2, SETX or SPATACSIN mutations. At present targeted resequencing with specific HSP- MND gene panels and targeted exome sequencing are in progress to complete the genetic characterization of the patients collected.

Biochemical and functional studies were also carried out in order to define the pathological effect of some of the mutated proteins identified in different families (Panzeri et al 2006, Crimella et al 2010, Airoldi et al 2010, Vantaggiato et al 2011, Vantaggiato et al 2013). Cellular models of neuronal and non- neuronal type were set and expertise was acquired in neuronal differentiation protocols by using P19 cell lines treated with retinoic acid (Vantaggiato et al 2009, Vantaggiato et al 2011). More recently, biochemical and functional characterization of fibroblasts derived from SPG15 mutated patients recently led to the identification of an autophagy defect in these cells (Vantaggiato et al 2013, Vantaggiato et al 2014). The results obtained indicate that Spastizin interacts with the autophagy related Beclin1-Uvrag-Rubicon multiprotein complex and is required for autophagosome maturation. In cells lacking Spastizin or with mutated forms of the protein, Spastizin interaction with Beclin1 is lost although the formation of the Beclin1-Uvrag-Rubicon complex can still be observed. However, in these cells we demonstrate an impairment of autophagosome maturation and an accumulation of immature autophagosomes. Autophagy defects with autophagosome accumulation can be observed also in neuronal cells by Spastizin silencing. These results indicate that autophagy is involved in the pathogenesis of complicated forms of hereditary spastic paraparesis with thin corpus callosum. We are now more deeply investigating these aspects in order to identify the molecular players involved in autophagosome maturation. We are also investigating the possible role of spastizin in endosomal trafficking and in the endo-lysosomal system.

Selected publications

• Scarlato M, Citterio A, Barbieri A, Godi C, Panzeri E, Bassi MT. Exome sequencing reveals a novel homozygous mutation in ACP33 gene in the first Italian family with SPG21. J Neurol. 2017 Jul 27. [Epub ahead of print]
• Martinuzzi A, Montanaro D, Vavla M, Paparella G, Bonanni P, Musumeci O, Brighina E, Hlavata H, Rossi G, Aghakhanyan G, Martino N, Baratto A, D'Angelo MG, Peruch F, Fantin M, Arnoldi A, Citterio A, Vantaggiato C, Rizzo V, Toscano A, Bresolin N, Bassi MT. Clinical and Paraclinical Indicators of Motor System Impairment in Hereditary Spastic Paraplegia: A Pilot Study. PLoS One. 2016 Apr 14;11(4):e0153283.
• Citterio A, Arnoldi A, Panzeri E, Merlini L, D'Angelo MG, Musumeci O, Toscano  A, Bondi A, Martinuzzi A, Bresolin N, Bassi MT. Variants in KIF1A gene in dominant and sporadic forms of hereditary spastic paraparesis. J Neurol. 2015 Dec;262(12):2684-90.
• Rinaldi F, Bassi MT, Todeschini A, Rota S, Arnoldi A, Padovani A, Filosto M. A novel mutation in motor domain of KIF5A associated with an HSP/axonal neuropathy  phenotype. J Clin Neuromuscul Dis. 2015 Mar;16(3):153-8.
• Perrotta C, Cervia D, De Palma C, Assi E, Pellegrino P, Bassi MT, Clementi E.  The emerging role of acid sphingomyelinase in autophagy. Apoptosis. 2015 May;20(5):635-44.
• Agosta F, Scarlato M, Spinelli EG, Canu E, Benedetti S, Bassi MT, Casali C,Sessa M, Copetti M, Pagani E, Comi G, Ferrari M, Falini A, Filippi M. Hereditary Spastic Paraplegia: Beyond Clinical Phenotypes toward a Unified Pattern of Central Nervous System Damage. Radiology. 2015 Jul;276(1):207-18.
• Vantaggiato C, Clementi E, Bassi MT. ZFYVE26/SPASTIZIN: a close link between complicated hereditary spastic paraparesis and autophagy. Autophagy. 2014 Feb;10(2):374-5.
• Vantaggiato C, Crimella C, Airoldi G, Polishchuk R, Bonato S, Brighina E, Scarlato M, Musumeci O, Toscano A, Martinuzzi A, Santorelli FM, Ballabio A, Bresolin N, Clementi E, Bassi MT. Defective autophagy in spastizin mutated patients with hereditary spastic paraparesis type 15. Brain. 2013 Oct;136(Pt 10):3119-39.
• Theofilopoulos S, Griffiths WJ, Crick PJ, Yang S, Meljon A, Ogundare M, Kitambi SS, Lockhart A, Tuschl K, Clayton PT, Morris AA, Martinez A, Reddy MA, Martinuzzi A, Bassi MT, Honda A, Mizuochi T, Kimura A, Nittono H, De Michele G, Carbone R, Criscuolo C, Yau JL, Seckl JR, Schüle R, Schöls L, Sailer AW, Kuhle J, Fraidakis MJ, Gustafsson JÅ, Steffensen KR, Björkhem I, Ernfors P, Sjövall J, Arenas E, Wang Y. Cholestenoic acids regulate motor neuron survival via liver X receptors. J Clin Invest. 2014 Nov 3;124(11):4829-42.
• Heinzen EL, Swoboda KJ, Hitomi Y, Gurrieri F, Nicole S, de Vries B, Tiziano FD, Fontaine B, Walley NM, Heavin S, Panagiotakaki E; European Alternating Hemiplegia of Childhood (AHC) Genetics Consortium; Biobanca e Registro Clinico per l'Emiplegia Alternante (I.B.AHC) Consortium; European Network for Research on Alternating Hemiplegia (ENRAH) for Small and Medium-sized Enterpriese (SMEs) Consortium, Fiori S, Abiusi E, Di Pietro L, Sweney MT, Newcomb TM, Viollet L, Huff C, Jorde LB, Reyna SP, Murphy KJ, Shianna KV, Gumbs CE, Little L, Silver K,  Ptáček LJ, Haan J, Ferrari MD, Bye AM, Herkes GK, Whitelaw CM, Webb D, Lynch BJ,  Uldall P, King MD, Scheffer IE, Neri G, Arzimanoglou A, van den Maagdenberg AM, Sisodiya SM, Mikati MA, Goldstein DB. De novo mutations in ATP1A3 cause alternating hemiplegia of childhood. Nat Genet. 2012 Sep;44(9):1030-4.
• Vantaggiato C, Bondioni S, Airoldi G, Bozzato A, Borsani G, Rugarli EI, Bresolin N, Clementi E, Bassi MT. Senataxin modulates neurite growth through fibroblast growth factor 8 signalling. Brain. 2011 Jun;134(Pt 6):1808-28.
• Crimella C, Baschirotto C, Arnoldi A, Tonelli A, Tenderini E, Airoldi G, Martinuzzi A, Trabacca A, Losito L, Scarlato M, Benedetti S, Scarpini E, Spinicci G, Bresolin N, Bassi MT. Mutations in the motor and stalk domains of KIF5A in spastic paraplegia type 10 and in axonal Charcot-Marie-Tooth type 2. Clin Genet.  2012 Aug;82(2):157-64.
• Crimella C, Cantoni O, Guidarelli A, Vantaggiato C, Martinuzzi A, Fiorani M, Azzolini C, Orso G, Bresolin N, Bassi MT. A novel nonsense mutation in the APTX gene associated with delayed DNA single-strand break removal fails to enhance sensitivity to different genotoxic agents. Hum Mutat. 2011 Apr;32(4):E2118-33.
• Arnoldi A, Crimella C, Tenderini E, Martinuzzi A, D'Angelo MG, Musumeci O, Toscano A, Scarlato M, Fantin M, Bresolin N, Bassi MT. Clinical phenotype variability in patients with hereditary spastic paraplegia type 5 associated with CYP7B1 mutations. Clin Genet. 2012 Feb;81(2):150-7.
• Panagiotakaki E, Gobbi G, Neville B, Ebinger F, Campistol J, Nevsímalová S, Laan L, Casaer P, Spiel G, Giannotta M, Fons C, Ninan M, Sange G, Schyns T, Vavassori R, Poncelin D; ENRAH Consortium, Arzimanoglou A. Evidence of a non-progressive course of alternating hemiplegia of childhood: study of a large cohort of children and adults. Brain. 2010 Dec;133(Pt 12):3598-610.
• De Palma C, Falcone S, Pisoni S, Cipolat S, Panzeri C, Pambianco S, Pisconti  A, Allevi R, Bassi MT, Cossu G, Pozzan T, Moncada S, Scorrano L, Brunelli S, Clementi E. Nitric oxide inhibition of Drp1-mediated mitochondrial fission is critical for myogenic differentiation. Cell Death Differ. 2010 Nov;17(11):1684-96.
• Airoldi G, Guidarelli A, Cantoni O, Panzeri C, Vantaggiato C, Bonato S, Grazia D'Angelo M, Falcone S, De Palma C, Tonelli A, Crimella C, Bondioni S, Bresolin N, Clementi E, Bassi MT. Characterization of two novel SETX mutations in AOA2 patients reveals aspects of the pathophysiological role of senataxin. Neurogenetics. 2010 Feb;11(1):91-100.
• Vantaggiato C, Redaelli F, Falcone S, Perrotta C, Tonelli A, Bondioni S, Morbin M, Riva D, Saletti V, Bonaglia MC, Giorda R, Bresolin N, Clementi E, Bassi MT. A novel CLN8 mutation in late-infantile-onset neuronal ceroid lipofuscinosis  (LINCL) reveals aspects of CLN8 neurobiological function. Hum Mutat. 2009 Jul;30(7):1104-16.
• Crimella C, Arnoldi A, Crippa F, Mostacciuolo ML, Boaretto F, Sironi M, D'Angelo MG, Manzoni S, Piccinini L, Turconi AC, Toscano A, Musumeci O, Benedetti S, Fazio R, Bresolin N, Daga A, Martinuzzi A, Bassi MT. Point mutations and a large intragenic deletion in SPG11 in complicated spastic paraplegia without thin corpus callosum. J Med Genet. 2009 May;46(5):345-51.
• Riano E, Martignoni M, Mancuso G, Cartelli D, Crippa F, Toldo I, Siciliano G, Di Bella D, Taroni F, Bassi MT, Cappelletti G, Rugarli EI. Pleiotropic effects of spastin on neurite growth depending on expression levels. J Neurochem. 2009 Mar;108(5):1277-88.
• De Palma C, Falcone S, Panzeri C, Radice S, Bassi MT, Clementi E. Endothelial nitric oxide synthase overexpression by neuronal cells in neurodegeneration: a link between inflammation and neuroprotection. J Neurochem. 2008 Jul;106(1):193-204.
• Arnoldi A, Tonelli A, Crippa F, Villani G, Pacelli C, Sironi M, Pozzoli U, D'Angelo MG, Meola G, Martinuzzi A, Crimella C, Redaelli F, Panzeri C, Renieri A, Comi GP, Turconi AC, Bresolin N, Bassi MT. A clinical, genetic, and biochemical characterization of SPG7 mutations in a large cohort of patients with hereditary  spastic paraplegia. Hum Mutat. 2008 Apr;29(4):522-31.
• Crippa F, Panzeri C, Martinuzzi A, Arnoldi A, Redaelli F, Tonelli A, Baschirotto C, Vazza G, Mostacciuolo ML, Daga A, Orso G, Profice P, Trabacca A, D'Angelo MG, Comi GP, Galbiati S, Lamperti C, Bonato S, Pandolfo M, Meola G, Musumeci O, Toscano A, Trevisan CP, Bresolin N, Bassi MT. Eight novel mutations in SPG4 in a large sample of patients with hereditary spastic paraplegia. Arch Neurol. 2006 May;63(5):750-5.
• Panzeri C, De Palma C, Martinuzzi A, Daga A, De Polo G, Bresolin N, Miller CC, Tudor EL, Clementi E, Bassi MT. The first ALS2 missense mutation associated with JPLS reveals new aspects of alsin biological function. Brain. 2006 Jul;129(Pt 7):1710-9.
• Bassi MT, Bresolin N, Tonelli A, Nazos K, Crippa F, Baschirotto C, Zucca C, Bersano A, Dolcetta D, Boneschi FM, Barone V, Casari G. A novel mutation in the ATP1A2 gene causes alternating hemiplegia of childhood. J Med Genet. 2004 Aug;41(8):621-8.
• Borgatti R, Zucca C, Cavallini A, Ferrario M, Panzeri C, Castaldo P, Soldovieri MV, Baschirotto C, Bresolin N, Dalla Bernardina B, Taglialatela M, Bassi MT. A novel mutation in KCNQ2 associated with BFNC, drug resistant epilepsy, and mental retardation. Neurology. 2004 Jul 13;63(1):57-65.

Partnerships

• Prof. Elena I. Rugarli, MD, Institute for Genetics, CECAD Research Center, University of Cologne, Joseph-Stelzmann-Str. 26, 50931 Köln, Germany
• Prof. William J. Griffiths, MRSC, CChem, Chair in Mass Spectrometry, Institute of Mass Spectrometry, College of Medicine, Grove Building Swansea University Singleton Park Swansea SA2 8PP, Wales, UK
• Prof G Borsani, Dott E. Giacopuzzi, Univ. di Brescia
• Dott. F.M. Santorelli , Laboratorio Medicina Molecolare, IRCCS Stella Maris, Pisa
• Prof. R Liguori, Clinica Neurologica, IRCCS Istituto delle Scienze Neurologiche, Università di Bologna, Pad G1 - Ospedale Bellaria, Via Altura 3, 40139 Bologna
• Prof. N Bresolin - Ospedale Maggiore Policlinico Fondazione Ca’ Granda, Università di Milano, Milano
• Prof A. Ballabio TIGEM, Pozzuoli (Napoli) 
• Dott R. Polishchuk , TIGEM,  Pozzuoli (Napoli)