Papers by Francesco Fornai
Journal of neural transmission, Feb 17, 2024
Methamphetamine (METH) produces a cytopathology, which is rather specific within catecholamine ne... more Methamphetamine (METH) produces a cytopathology, which is rather specific within catecholamine neurons both in vitro and ex vivo, in animal models and chronic METH abusers. This led some authors to postulate a sort of parallelism between METH cytopathology and cell damage in Parkinson's disease (PD). In fact, METH increases and aggregates alpha-syn proto-fibrils along with producing spreading of alpha-syn. Although alpha-syn is considered to be the major component of aggregates and inclusions developing within diseased catecholamine neurons including classic Lewy body (LB), at present, no study provided a quantitative assessment of this protein in situ, neither following METH nor in LB occurring in PD. Similarly, no study addressed the quantitative comparison between occurrence of alpha-syn and other key proteins and no investigation measured the protein compared with non-protein structure within catecholamine cytopathology. Therefore, the present study addresses these issues using an oversimplified model consisting of a catecholamine cell line where the novel approach of combined light and electron microscopy (CLEM) was used measuring the amount of alpha-syn, which is lower compared with p62 or poly-ubiquitin within pathological cell domains. The scenario provided by electron microscopy reveals unexpected findings, which are similar to those recently described in the pathology of PD featuring packing of autophagosome-like vesicles and key proteins shuttling autophagy substrates. Remarkably, small seed-like areas, densely packed with p62 molecules attached to poly-ubiquitin within wide vesicular domains occurred. The present data shed new light about quantitative morphometry of catecholamine cell damage in PD and within the addicted brain.
Italian journal of anatomy and embryology, 2011
Neurotoxicity Research, Nov 18, 2020
The neurotoxin 1-methyl, 4-phenyl, 1, 2, 3, 6-tetrahydropiridine (MPTP) is widely used to produce... more The neurotoxin 1-methyl, 4-phenyl, 1, 2, 3, 6-tetrahydropiridine (MPTP) is widely used to produce experimental parkinsonism. Such a disease is characterized by neuronal damage in multiple regions beyond the nigrostriatal pathway including the spinal cord. The neurotoxin MPTP damages spinal motor neurons. So far, in Parkinson's disease (PD) patients alpha-synuclein aggregates are described in the dorsal horn of the spinal cord. Nonetheless, no experimental investigation was carried out to document whether MPTP affects the sensory compartment of the spinal cord. Thus, in the present study, we investigated whether chronic exposure to small doses of MPTP (5 mg/kg/X2, daily, for 21 days) produces any pathological effect within dorsal spinal cord. This mild neurotoxic protocol produces a damage only to nigrostriatal dopamine (DA) axon terminals with no decrease in DA nigral neurons assessed by quantitative stereology. In these experimental conditions we documented a decrease in enkephalin-, calretinin-, calbindin D28K-, and parvalbumin-positive neurons within lamina I and II and the outer lamina III. Met-Enkephalin and substance P positive fibers are reduced in laminae I and II of chronically MPTP-treated mice. In contrast, as reported in PD patients, alphasynuclein is markedly increased within spared neurons and fibers of lamina I and II after MPTP exposure. This is the first evidence that experimental parkinsonism produces the loss of specific neurons of the dorsal spinal cord, which are likely to be involved in sensory transmission and in pain modulation providing an experimental correlate for sensory and pain alterations in PD.
Italian journal of anatomy and embryology, 2016
Neuroscience & Biobehavioral Reviews, May 1, 2023
Frontiers in Neuroscience, Nov 24, 2016
Mammalian retromers play a critical role in protein trans-membrane sorting from endosome to the t... more Mammalian retromers play a critical role in protein trans-membrane sorting from endosome to the trans-Golgi network (TGN). Recently, retromer alterations have been related to the onset of Parkinson's Disease (PD) since the variant p.Asp620Asn in VPS35 (Vacuolar Protein Sorting 35) was identified as a cause of late onset PD. This variant causes a primary defect in endosomal trafficking and retromers formation. Other mutations in VPS genes have been reported in both sporadic and familial PD. These mutations are less defined. Understanding the specific prevalence of all VPS gene mutations is key to understand the relevance of retromers impairment in the onset of PD. A number of PD-related mutations despite affecting different biochemical systems (autophagy, mitophagy, proteasome, endosomes, protein folding), all converge in producing an impairment in cell clearance. This may explain how genetic predispositions to PD may derive from slightly deleterious VPS mutations when combined with environmental agents overwhelming the clearance of the cell. This manuscript reviews genetic data produced in the last 5 years to redefine the actual prevalence of VPS gene mutations in the onset of PD. The prevalence of p.Asp620Asn mutation in VPS35 is 0.286 of familial PD. This increases up to 0.548 when considering mutations affecting all VPS genes. This configures mutations in VPS genes as the second most frequent autosomal dominant PD genotype. This high prevalence, joined with increased awareness of the role played by retromers in the neurobiology of PD, suggests environmentally-induced VPS alterations as crucial in the genesis of PD.
Prion, Jul 1, 2011
T he prion protein is a glycoprotein characterized by a folded α-helical structure that, under pa... more T he prion protein is a glycoprotein characterized by a folded α-helical structure that, under pathological conditions, misfolds and aggregates into its infectious isoform as β-sheet rich amyloidic deposits. The accumulation of the abnormal protein is responsible for a group of progressive and fatal disorders characterized by vacuolation, gliosis and spongiform degeneration. Prion disorders are characterized by a triple aetiology: familial, sporadic or acquired, although most cases are sporadic. The mechanisms underlying prion neurotoxicity remain controversial, while novel findings lead to hypothesize intriguing pathways responsible for prion spreading. The present review aims to examine the involvement of the gastrointestinal tract and hypothesizes the potential mechanisms underlying cell-to-cell transmission of the prion protein. In particular, a special emphasis is posed on the mechanisms of prion transmission within the gut and towards the central nervous system. The glycation of prion protein to form advanced glycation endproducts (AGE) interacting with specific receptors placed on neighboring cells (RAGE) represents the key hypothesis to be discussed. ©2 0 1 1 L a n d e s B i o s c i e n c e. D o n o t d i s t r i b u t e .
The Journal of Neuroscience, Mar 15, 2002
Methamphetamine (MA), a widely used drug of abuse, produces oxidative damage of nigrostriatal dop... more Methamphetamine (MA), a widely used drug of abuse, produces oxidative damage of nigrostriatal dopaminergic terminals. We examined the effect of subtype-selective ligands of metabotropic glutamate (mGlu) receptors on MA neurotoxicity in mice. MA (5 mg/kg, i.p.; injected three times, every 2 hr) induced, 5 d later, a substantial degeneration of striatal dopaminergic terminals associated with reactive gliosis. MA toxicity was primarily attenuated by the coinjection of the noncompetitive mGlu5 receptor antagonists 2-methyl-6-(phenylethynyl)pyridine and (E)-2-methyl-6styrylpyridine both at 10 mg/kg, i.p.). In contrast, the mGlu1 receptor antagonist 7-(hydroxyimino)cyclopropa[b]chromen-1acarboxylate ethyl ester (10 mg/kg, i.p.), and the mGlu2/3 receptor agonist (Ϫ)-2-oxa-4-aminocyclo[3.1.0]hexane-4,6-dicarboxylic acid (1 mg/kg, i.p.), failed to affect MA toxicity. mGlu5 receptor antagonists reduced the production of reactive oxygen species but did not reduce the acute stimulation of dopamine release induced by MA both in striatal synaptosomes and in the striatum of freely moving mice. We conclude that endogenous activation of mGlu5 receptors enables the development of MA neurotoxicity and that mGlu5 receptor antagonists are neuroprotective without interfering with the primary mechanism of action of MA.
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Papers by Francesco Fornai