Pathogenesis of neurological and neuromuscular diseases


Brain folding diseases, including Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis (ALS), and polyglutamine diseases, are a broad class of neurodegenerative disorders characterized by selective degeneration of specific neuronal populations in the central nervous system. The basis for selective neuronal vulnerability remains an enigma. Polyglutamine diseases are a family of nine neurodegenerative diseases, including spinal and bulbar muscular atrophy (SBMA), Huntington’s disease (HD), DRPLA, and six types of spinocerebellar ataxia. Polyglutamine diseases are caused by expansions of the CAG trinucleotide repeat encoding a polyglutamine tract in the coding region of specific genes. Amyotrophic lateral sclerosis (ALS) is characterized by the selective loss of upper and lower motor neurons and skeletal muscle atrophy, wasting and paralysis with death of patients occurring in about two-to-five years from diagnosis. Our laboratory focuses on the elucidation of the molecular mechanisms underlying the degeneration and death of neurons with the aim to develop novel potential therapeutic strategies for these incurable disorders. We investigate the relevance of the functional relationship between protein function and structure on disease pathogenesis. We aim at identifying post-translational modifications (PTMs) of the disease proteins that either enhance or suppress neurodegeneration, and use this information to identify drugs that activate cellular pathways that target the disease protein for therapy development. Using inducible animal models of SBMA for spatial and temporal control of expression of the disease protein, we explore the role of peripheral tissues, such as skeletal muscle, in the pathogenesis of neuromuscular diseases. In addition, we investigate the molecular details of communication between neurons and non-neuronal cells and the relevance of metabolic tissues in neuromuscular diseases. 

Five recent publications

  • Polanco MJ, Parodi S, Piol D, Stack C, Chivet M, Contestabile A, Miranda HC, Lievens PMJ, Espinoza S, Jochum T, Rocchi A, Grunseich C, Gainetdinov RR, Cato ACB, Lieberman A, La Spada AR, Sambataro F, Fischbeck KH, Gozes I, Pennuto M*. (2016) CDK2 inhibition by PACAP/AC/PKA signaling reduces polyglutamine-expanded androgen receptor phosphorylation and toxicity in SBMA. Sci Transl Med 8:370ra181. 
  • Rocchi A, Milioto C, Parodi S, Armirotti A, Borgia D, Pellegrini M, Urciuolo A, Molon S, Morbidoni V, Marabita M, Romanello V, Gatto P, Blaauw B, Bonaldo P, Sambataro F, Robins DM, Lieberman AP, Sorarù G, Vergani L, Sandri M, Pennuto M*. (2016) Glycolytic-to-oxidative fiber-type switch and mTOR signaling activation are early-onset features of SBMA muscle modified by high-fat diet. Acta Neuropathol 132:127-44.
  • Scaramuzzino C, Casci I, Parodi S, Lievens PMJ, Polanco MJ, Milioto C, Chivet M, Monaghan J, Mishra A, Badders N, Aggarwal T, Grunseich C, Sambataro F, Basso M, Fackelmayer FO, Taylor JP, Pandey UB, Pennuto M*. (2015) Protein arginine methyltransferase 6 enhances polyglutamine-expanded androgen receptor function and toxicity in spinal and bulbar muscular atrophy. Neuron 85: 88-100.
  • Palazzolo I, Stack C, Kong L, Musaro M, Adachi H, Katsuno M, Sobue G, Taylor JP, Sumner JC, Fischbeck HK, Pennuto M* (2009) Overexpression of muscle-specific isoform of IGF-1 in the skeletal muscle of SBMA mice extends life and attenuates disease manifestations. Neuron 63: 316-28.
  • Pennuto M, Tinelli E, Malaguti M, Del Carro U, D'Antonio M, Ron D, Quattrini A, Feltri ML, Wrabetz L. (2008) Ablation of the UPR-mediator CHOP restores motor function and reduces demyelination in Charcot-Marie-Tooth 1B mice. Neuron 57:393-405. 


  • Muscular Dystrophy Association (USA)
  • Muscular Dystrophy Association (AFM French)
  • Akira Arimura Foundation (Japan)
  • BIRD-DBS University of Padova (Italy)
  • Ministry of Health (Italy)