The Unit of Genetics of Neurodegenerative disorders belongs to the Laboratory of Biology of Neurodegenerative Disorders, Department of Neuroscience (Laboratory and Department Head: Dr Gianluigi Forloni, PhD) and is located at the Mario Negri Institute for Pharmacological Research in Milan, Italy. The Institute moved from its historical location in 2007 and it is now in a new, exciting scientific and academic environment (Bovisa Sud Campus).
The Mario Negri Institute offers a scientific expertise in several field of medicine, environmental science and pharmacology (for more info, visit www.marionegri.it)
Diego Albani is a researcher who coordinates a team involved in age-associated neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease and frontotemporal dementia. The main topics are genetics, oxidative stress, cellular and in vivo models of neurodegeneration.
We are always willing to evaluate applications from young, higly motivated graduated or doctoral fellows from any country that are fascinated from neuroscience and neurodegeneration in particular.
Armando Chierchia, fellow
Research expertise: in vitro and in vivo models of Alzheimer's disease - genetics - environmental enrichment protocols- mesenchymal and iPS stemm cells
Serena Rodilossi, fellow
Research expertise: mesencephalic and cortical primary cultures from rodent - in vivo models of dopaminergic degeneration
Gloria Biella, PhD student
Research expertise: pharmacogenomics - exosome trafficking - in vivo models of tau protein deposition
Ottavia Bernocchi, ungraduated student
Research expertise: cloning, protein expression and oxidative stress models
Alice Ghilardi, ungraduated student
Research expertise: aging, protein expression and in vitrto models
Marta Tunesi PhD, visiting scientist
Research expertise: hydrogel matrices and in vitro model of protein release
Here is enclosed a short description of the devastating pathologies whose therapy is currently a main goal of the research worldwide that are the topic of our experimental point-of-view.
Alzheimer’s disease (AD) is a neurodegenerative process affecting the elderly and the number of AD patients is expected to raise in the next decades. Almost all AD cases are sporadic and only less than 5% has a monogenic basis. The main clinical feature of AD is memory loss. During the disease progression, most AD patients develop behavioral and psychological symptoms of dementia (BPSD). BPSD encompass agitation, aggression, sexual disinhibition, delusions, hallucinations and sleeping or eating disorders.
The genetic aspect of AD etiopathogenesis has been widely investigated since the discovery of beta-amyloid precursor protein (betaAPP) mutations linked to hereditary cases of AD. To date, several mutations in three genes (betaAPP, presenilin-1 [PSEN-1] and presenilin-2 [PSEN-2]) have been linked to familial forms of AD; PSEN-1 mutations are the most frequent and fully penetrant. Typical features of PSEN-1 pathogenic mutations are the autosomal dominant pattern of inheritance, early onset of the pathology (<65 years) and an increase of Abeta(1-42) production.
The available AD therapy is only symptomatic, mainly based on acetylcholinesterase inhibitors (Donepezil - Rivastigmine). A novel approach has been recently described by the mithocondrial-acting drug Dimebon.
In our lab we are devoted to the genetic variants that are causative of familial AD or predispose to the sporadic form of the pathology (apolipoprotein E epsilon-4 being the most widely recognized).
Parkinson’s disease (PD) is a neurodegenerative, multifactorial movement disorder affecting about 3% of the population over 65 years. To date, six different casual genes linked to rare familiar forms of PD have been identified, with few evident functional interactions. Consequently, a major question is the relationship between these proteins whose alteration leads ultimately to a similar pathology. Genetic modifications in the proteins coded by the family-PD-linked genes PARK-1 [alias a-synuclein (a-syn); GenBank: NM_000345;OMIM: #168600] and PARK-7 (alias DJ-1; GenBank: NM_007262; OMIM: #606324) cause respectively an autosomal dominant and an autosomal recessive form of PD.
A-syn physiologic function is unclear, but the protein is present in Lewy bodies (LB), a PD hallmark. An a-syn-dependent etiopathologic hypothesis states that in PD a-syn is able to aggregate and gain a toxic function, even if the noxious aggregated form (protofibrillar or fibrillar) is debated. Transgenic models developed to support this hypothesis resulted in mild to severe phenotypes. A-syn gene multiplication has been associated with familial PD. Other data support an alternative scenario where a-syn aggregation prevents the protein performing its physiological neuroprotective functions that deal with chaperone-like activity, dopamine homeostasis and correct synaptic vesicular trafficking. A-syn null mice did not show a severe phenotype, suggesting that loss of function alone is not sufficient to explain the pathogenesis.
DJ-1 mutations are single-nucleotide substitutions or deletions leading to a non-functional protein. DJ-1 alterations are more frequent than a-syn mutations; consequently, DJ-1 has been evaluated as a genetic predisposing factor for sporadic PD though with mainly negative results. Information on DJ-1 function in the nervous system deals with antioxidant activity, chaperone-like properties, involvement in mitochondrial physiology and dopamine homeostasis.
We have deeply investigated the relationship between a-syn, DJ-1 and HSP70 and we are now trying to use DJ-1 as a neuroprotective drug to counteract PD progression.
Frontotemporal dementia, or frontotemporal lobar degeneration (FTLD) is a neurodegenerative disease characterized by alterations in behavior and speech. The majority of FTLD cases are sporadic and only a minor fraction (5-10%) is monogenic due to alterations in the microtubule-associated protein tau (MAPT, OMIM +157140), granulin (GRN, OMIM *138945), valosin-containing protein (VCP, OMIM *601023) or the chromatin modifying protein 2B (CHMP2B, OMIM +609512).
The current consensus criteria identify three clinical FTLD subtypes: progressive nonfluent aphasia (PA), semantic dementia (SD) and frontotemporal dementia (FTD). Few genes have been considered as genetic susceptibility factors for sporadic FTLD, including MAPT itself
An imbalance in serotonin transmission has been reported in FTLD patients. In our group we have investigated this aspect from the genetic point of view, finding an interesting association between a functional polymorphism of the serotonin transporter gene and FTLD susceptibility.