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Maria Pennuto, PhD
Professor of Molecular Biology
Schaller Foundation/FENS-Kavli Network of Excellence (FKNE) Alumna
Dulbecco Telethon Institute Alumna
Marie Curie Alumna

Current position
2025-present Professor of Molecular Biology, Department of Biomedical Sciences (DBS), University of Padova, Padova, Italy

2018-present Group Leader, Veneto Institute of Molecular Medicine (VIMM), Padova, Italy

Place of work
Department of Biomedical Sciences (DBS), University of Padova, Italy
via Ugo Bassi 58/B, 35131 Padova, Italia
Phone: Office +39 049 827 6069, Lab +39 049 827 6057
email maria.pennuto@unipd.it & pennutom@gmail.com
Website: http://www.biomed.unipd.it/ricerca/aree-tematiche/neuroscience/pathogenesis-neurological-and-neuromuscular-diseases

Veneto Institute of Molecular Medicine (VIMM)
via Orus 2, 35129 Padova, Italy
Phone: Office +39 049 7923258, Lab +39 049 7923268
website: http://www.vimm.it/scientific-board/maria-pennuto

Identification codes
ORCID ID orcid.org/0000-0001-8634-0767
Scopus Author ID 55897284500
Loop profile 122871
Research ID E-3270-2019

Prof. Maria Pennuto graduated with honors in Biological Sciences from La Sapienza University of Rome in 1996. She earned her PhD in Cellular and Molecular Biology at the University of Milan in 2000 under the supervision of Prof. F. Valtorta.

From 2001 to 2004, she pursued postdoctoral research in the laboratory of Dr. L. Wrabetz at San Raffaele, Milan, investigating the molecular mechanisms of Charcot–Marie–Tooth disease type 1B. She then moved to the National Institute of Neurological Disorders and Stroke (NINDS), NIH (USA), where, as a visiting postdoctoral fellow in Dr. K. Fischbeck’s laboratory (2005–2008), she studied the molecular bases of motor neuron diseases. In 2008, she was appointed Staff Scientist in the Department of Neurology at the University of Pennsylvania (Philadelphia, USA), continuing her work on neurodegenerative disorders.

In 2009, Dr. Pennuto returned to Italy as an independent researcher at the Italian Institute of Technology (IIT), Genoa, where she led a research unit focused on the molecular mechanisms of neuromuscular diseases such as SBMA and ALS. Her scientific achievements were recognized in 2013 with the Dulbecco Telethon Lifetime Achievement Award, and she was appointed Telethon Scientist. That same year, she joined the University of Trento as a tenure-track researcher (Type B, SSD: BIO/11 – Molecular Biology), where she was promoted to Associate Professor in 2016.

Since 2017, Prof. Pennuto has been Associate Professor of Molecular Biology at the University of Padua, where she coordinates and teaches courses in Molecular Biology for the degree programs in Medicine and Surgery (Padua and Treviso) and Data Science (English track). She leads a dynamic research group of 12 members. In parallel, she has been head of unit at the Veneto Institute of Molecular Medicine (VIMM) since 2018, serving also as Deputy Director of the Institute from 2018 to 2023.

In 2025, Prof. Pennuto was promoted to Full Professor of Molecular Biology at the University of Padua.

C. Contributions to Science:
1. Post-translational modifications in age-related diseases. Spinal and bulbar muscular atrophy (SBMA) is a neuromuscular disease caused by polyglutamine expansion in the androgen receptor (AR). SBMA belongs to the family of polyglutamine diseases, which also includes Huntington's disease, DRPLA, and six types of spinocerebellar ataxia. We showed that polyglutamine-expanded androgen receptor (polyQ-AR) is phosphorylated by Akt/PKB as well as CDKs. Phosphorylation of polyQ-AR by Akt reduced androgen binding and toxicity, whereas phosphorylation by the CDKs has the opposite effect. Moreover, we showed that phosphorylation by Akt is mutually exclusive with arginine methylation by protein arginine methyltransferase 6 (PRMT6). We identified PRMT6 and LSD1 as novel co-activators of normal AR, whose function was enhanced by polyQ expansion. Inhibition of PRMT6 and LSD1 reduced the toxicity of polyQ-AR, indicating that these epigenetic writers are novel modifiers of SBMA pathogenesis. We identified signaling pathways that enhance AR PTMs and suppress toxicity in preclinical models, linking our findings to development of novel therapeutics. Thus, we validated our experimental approach to identify post-translational modifications that impact (enhance or suppress) toxicity and to use this information to screen for agents that modulate such modifications for therapeutic purposes.
a) Piol, et al., Pennuto M*. Antagonistic effect of cyclin-dependent kinases and a calcium-dependent phosphatase on polyglutamine-expanded AR toxic gain-of-function. Sci. Adv. (in press).
b) Prakasam, et al, Pennuto M*. Lysine demethylase 1 and protein arginine methyltransferase 6 synergistically escalate androgen receptor toxic gain of function causing neurodegeneration. Nature Comm 14:603.
c) 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*. CDK2 inhibition by PACAP/AC/PKA signaling reduces polyglutamine-expanded androgen receptor phosphorylation and toxicity in SBMA. Sci Transl Med 2016, 8:370ra181.
d) Scaramuzzino C, Casci I, Parodi S, Lievens P, Polanco M, Milioto C, Chivet M, Monaghan J, Mishra A, Badders N, Aggarwal T, Grunseich C, Sambataro F, Basso M, Fackelmayer F, Taylor J, Pandey U, Pennuto M*. Protein Arginine Methyltransferase 6 Enhances Polyglutamine-Expanded Androgen Receptor Function and Toxicity in Spinal and Bulbar Muscular Atrophy. Neuron 2015, 85:88-100.

2. Role of peripheral tissues in neurodegenerative diseases. We showed that skeletal muscle is a primary site of toxicity of polyQ-expanded AR. In detail, we demonstrated that SBMA muscles undergo an early glycolytic-to-oxidative fiber-type switch, metabolic alterations, dysregulation of ECC and contractile gene expression, and altered mitochondrial respiration, followed by accumulation of calcium into mitochondria, membrane depolarization, disruption of myofiber structure and ultimate degeneration of the NMJs. All these phenotypes were androgen-dependent, and reversible. These findings indicate that muscle is a viable therapeutic target for SBMA and provide proof-of-principle that intervention designed to target muscle has remarkable effects on spinal cord pathology.
a) Marchioretti, et al., Pennuto M*. Defective excitation-contraction coupling and mitochondrial respiration precede mitochondrial Ca2+ accumulation in spinobulbar muscular atrophy skeletal muscle. Nature Comm 14:602.
b) 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*. Glycolytic-to-oxidative fiber-type switch and mTOR signaling activation are early-onset features of SBMA muscle modified by high-fat diet. Acta Neuropathol 2016.132: 127-44.
c) Palazzolo I, Stack C, Kong L, Musaro A, Adachi H, Katsuno M, Sobue G, Taylor J, Sumner C, Fischbeck K, Pennuto M*. Overexpression of IGF-1 in Muscle Attenuates Disease in a Mouse Model of Spinal and Bulbar Muscular Atrophy. Neuron. 2009, 63:316-328.

3. Between 2001-2004, I expanded my interests from basic to translational neuroscience. During my first post-doctoral experience (2001-2004, Mentor Dr Lawrence Wrabetz) I studied the pathogenetic mechanisms that cause Charcot-Marie-Tooth type 1B (CMT1B) peripheral neuropathy. I showed that deletion of serine 63 in the myelin protein zero (MP0) causes protein unfolding, retention in the endoplasmic reticulum and induction of a stress response, i.e. the unfolded protein response (UPR). Deletion of one of the UPR effectors, CHOP transcription factor, rescued neurodegeneration and motor function. Our results indicate that mutant MP0 causes demyelination through a toxic gain of function mechanism in the endoplasmic reticulum (without arriving to the myelin sheet). Moreover, I showed that other MP0 mutants caused disease through similar mechanism if retained in the reticulum, extending the impact of these findings.
a) Saporta MA, Shy BR, Patzko A, Bai Y, Pennuto M, Ferri C, Tinelli E, Saveri P, Kirschner D, Crowther M, Southwood C, Wu X, Gow A, Feltri ML, Wrabetz L, Shy ME. MpzR98C arrests Schwann cell development in a mouse model of early-onset Charcot-Marie-Tooth disease type 1B. Brain. 2012; 135:2032-47.
b) Pennuto M, Tinelli E, Malaguti M, Del Carro U, D'Antonio M, Ron D, Quattrini A, Feltri ML, Wrabetz L. Ablation of the UPR-mediator CHOP restores motor function and reduces demyelination in Charcot-Marie-Tooth 1B mice. Neuron. 2008; 57:393-405.
c) Wrabetz L, D'Antonio M, Pennuto M, Dati G, Tinelli E, Fratta P, Previtali S, Imperiale D, Zielasek J, Toyka K, Avila RL, Kirschner DA, Messing A, Feltri ML, Quattrini A. Different intracellular pathomechanisms produce diverse Myelin Protein Zero neuropathies in transgenic mice. J Neurosci. 2006; 26:2358-68.


4. During my PhD (1997-2000, Mentor Prof Flavia Valtorta), I investigated the molecular mechanisms of synaptic vesicle (SV) neurotransmission in living neurons. Synaptophysin I (SypI) and Synaptobrevin 2 (VAMP2) are very abundant SV proteins. I tested the hypothesis that SypI regulates VAMP2 availability for exocytosis and sorting. SypI and VAMP2 form both homo- and hetero-oligomers. Using FRET, I showed that SypI oligomers disassemble upon complete fusion of SVs, whereas SypI-VAMP2 oligomers disassemble before massive exocytosis. Overexpression of VAMP2 in hippocampal neurons resulted in diffused distribution along the axon. Co-expression of SypI restored the correct sorting of VAMP2, but not VAMP1 and Synaptotagmin I, indicating that SypI specifically regulates the sorting of VAMP2 to synaptic boutons.
a. Bonanomi D, Pennuto M, Rigoni M, Rossetto O, Montecucco C, Valtorta F. Taipoxin induces synaptic vesicle exocytosis and disrupts the interaction of synaptophysin I with VAMP2. Mol Pharmacol 2005, 67:1901-8.
b. Rigoni M, Schiavo G, Weston AE, Caccin P, Allegrini F, Pennuto M, Valtorta F, Montecucco C, Rossetto O. Snake presynaptic neurotoxins with phospholipase A2 activity induce punctate swellings of neurites and exocytosis of synaptic vesicles. J Cell Sci 2004,117:3561-70.
c. Pennuto M, Bonanomi D, Benfenati F, Valtorta F. Synaptophysin I controls the targeting of VAMP2/synaptobrevin II to synaptic vesicles. Mol Biol Cell 2003, 14:4909-19.
d. Pennuto M. Dunlap D, Contestabile A, Benfenati F, Valtorta F. Fluorescence Resonance Energy Transfer Detection of Synaptophysin I and Vesicle- associated Membrane Protein 2 Interactions during Exocytosis from Single Live Synapses. Mol Biol Cell 2002; 13:2706-2717.

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https://pubmed.ncbi.nlm.nih.gov/?term=pennuto+m&sort=date&size=50

Brain folding diseases, including Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis (ALS), and polyglutamine diseases, are a broad class of neurodegenerative disorders. These diseases are 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 expansion of the CAG repeat encoding glutamine 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 three-five years from diagnosis. The majority of cases are sporadic (sALS), while a restricted number of cases is familial (fALS). sALS is a complex disease that is thought to result from the interplay between environmental and genetic factors. 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.Using SBMA and HD as models of polyglutamine diseases and motor neuron disease, we study 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 to induce or attenuate such PTMs 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, to 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.

Molecular mechanisms of neurodegenerative diseases and cancers with sex bias