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Masato, Anna (2019) DOPAL-induced impairment of aSynuclein and cellular proteostasis as molecular mechanism to enhance neuronal vulnerability in Parkinson's disease. [Ph.D. thesis]

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Abstract (italian or english)

Parkinson’s Disease (PD) is pathologically characterized by the progressive loss of nigrostriatal dopaminergic neurons and aberrant accumulation of the pre-synaptic protein aSynuclein (aSyn). Several factors have been proposed to trigger aSyn aggregation, resulting aSyn-induced neurotoxicity. Here, the working hypothesis is to assess how the interplay between aSyn and an altered dopamine metabolism may contribute to the pathogenesis of PD. A relevant role has been assigned to the dopamine metabolite 3,4-dihydroxyphenylacetaldehyde (DOPAL), whose neurotoxic action has been supported by several experimental models. Being an aldehyde, DOPAL covalently modifies lysine residues of proteins, thus aSyn is considered a preferential target due to the high percentage of lysines in its sequence, its unfolded state and abundance at synapses. In vitro and cellular studies demonstrated that DOPAL triggers aSyn oligomerization, prevents aSyn association to synaptic vesicle membranes and affects synapse physiology. Of note, some lysines on aSyn sequence that were identified as DOPAL-modified, are also reported as target of functional post-translational modifications that regulate aSyn proteostasis.
On this ground, we aimed to investigate the consequences of DOPAL build-up in neurons on both aSyn and cellular proteostasis, in a wider perspective. To address these issues, cellular biology and biochemical studies were coupled with advanced imaging techniques, like the correlated light and electron microscopy (CLEM), which allows to map the aSyn localization, both at cellular and supra-molecular level. As cellular models, we worked on both rat primary cortical neurons and the catecholaminergic BE(2)-M17 cells.
Here, we provided evidence of a DOPAL-dependent aSyn redistribution in the neuronal compartments, from the peripheral terminals to its axonal trafficking to the soma. These observations were also linked to the assessment of aSyn affected clearance in the presence of DOPAL. Interestingly, DOPAL appeared to promote the aSyn loading in the multi-vesicular bodies (MVBs) of the endosomal pathway and the aSyn accumulation within perinuclear lysosomes, both in its monomeric and oligomeric forms.
Since aSyn oligomers are known to affect protein degradation systems functionality, we aimed to unravel the hypothesis of a synergistic effect of aSyn and DOPAL on a general impairment of cellular proteostasis. Indeed, increasing concentrations of DOPAL treatment in BE(2)-M17 cells led to a dose-dependent accumulation of ubiquitinated proteins and the autophagic marker p62, suggesting a potential impairment of the proteasome and the autophagic flux, respectively.
Finally, we recently started to explore a translational approach to control DOPAL-associated toxicity. Specifically, we used biguanidine molecules as aldehyde scavengers, i.e. aminoguanidine and metformin, that are already in clinical practice. So far, preliminary experiments confirmed the ability of aminoguanidine to slow-down DOPAL-induced aSyn in vitro oligomerization. Also, both aminoguanidine and metformin treatments reduced the accumulation of p62 caused by DOPAL in BE(2)-M17. Given these promising results, the beneficial effect of these compounds against the DOPAL-associated neurotoxicity will be further investigated.
In conclusion, DOPAL build-up in the cellular environment causes impaired aSyn trafficking, aSyn aggregation and decreased clearance. At the same time, DOPAL appears to affect protein degradation systems functionality, which would result in overall impaired neuronal proteostasis. Finally, the DOPAL-induced overload in MVBs together with the blockage of autophagy might promote the secretion of DOPAL-modified aSyn through exosomes, spreading these toxic species in the surrounding environment. On this ground, a therapeutic approach to target DOPAL neurotoxicity on site and to promote protein turnover might be of interest.

Abstract (a different language)

Parkinson’s Disease (PD) is pathologically characterized by the progressive loss of nigrostriatal dopaminergic neurons and aberrant accumulation of the pre-synaptic protein aSynuclein (aSyn). Several factors have been proposed to trigger aSyn aggregation, resulting aSyn-induced neurotoxicity. Here, the working hypothesis is to assess how the interplay between aSyn and an altered dopamine metabolism may contribute to the pathogenesis of PD. A relevant role has been assigned to the dopamine metabolite 3,4-dihydroxyphenylacetaldehyde (DOPAL), whose neurotoxic action has been supported by several experimental models. Being an aldehyde, DOPAL covalently modifies lysine residues of proteins, thus aSyn is considered a preferential target due to the high percentage of lysines in its sequence, its unfolded state and abundance at synapses. In vitro and cellular studies demonstrated that DOPAL triggers aSyn oligomerization, prevents aSyn association to synaptic vesicle membranes and affects synapse physiology. Of note, some lysines on aSyn sequence that were identified as DOPAL-modified, are also reported as target of functional post-translational modifications that regulate aSyn proteostasis.
On this ground, we aimed to investigate the consequences of DOPAL build-up in neurons on both aSyn and cellular proteostasis, in a wider perspective. To address these issues, cellular biology and biochemical studies were coupled with advanced imaging techniques, like the correlated light and electron microscopy (CLEM), which allows to map the aSyn localization, both at cellular and supra-molecular level. As cellular models, we worked on both rat primary cortical neurons and the catecholaminergic BE(2)-M17 cells.
Here, we provided evidence of a DOPAL-dependent aSyn redistribution in the neuronal compartments, from the peripheral terminals to its axonal trafficking to the soma. These observations were also linked to the assessment of aSyn affected clearance in the presence of DOPAL. Interestingly, DOPAL appeared to promote the aSyn loading in the multi-vesicular bodies (MVBs) of the endosomal pathway and the aSyn accumulation within perinuclear lysosomes, both in its monomeric and oligomeric forms.
Since aSyn oligomers are known to affect protein degradation systems functionality, we aimed to unravel the hypothesis of a synergistic effect of aSyn and DOPAL on a general impairment of cellular proteostasis. Indeed, increasing concentrations of DOPAL treatment in BE(2)-M17 cells led to a dose-dependent accumulation of ubiquitinated proteins and the autophagic marker p62, suggesting a potential impairment of the proteasome and the autophagic flux, respectively.
Finally, we recently started to explore a translational approach to control DOPAL-associated toxicity. Specifically, we used biguanidine molecules as aldehyde scavengers, i.e. aminoguanidine and metformin, that are already in clinical practice. So far, preliminary experiments confirmed the ability of aminoguanidine to slow-down DOPAL-induced aSyn in vitro oligomerization. Also, both aminoguanidine and metformin treatments reduced the accumulation of p62 caused by DOPAL in BE(2)-M17. Given these promising results, the beneficial effect of these compounds against the DOPAL-associated neurotoxicity will be further investigated.
In conclusion, DOPAL build-up in the cellular environment causes impaired aSyn trafficking, aSyn aggregation and decreased clearance. At the same time, DOPAL appears to affect protein degradation systems functionality, which would result in overall impaired neuronal proteostasis. Finally, the DOPAL-induced overload in MVBs together with the blockage of autophagy might promote the secretion of DOPAL-modified aSyn through exosomes, spreading these toxic species in the surrounding environment. On this ground, a therapeutic approach to target DOPAL neurotoxicity on site and to promote protein turnover might be of interest.

EPrint type:Ph.D. thesis
Tutor:Bubacco, Luigi
Supervisor:Boassa, Daniela
Ph.D. course:Ciclo 32 > Corsi 32 > BIOSCIENZE > BIOLOGIA CELLULARE E FISIOLOGIA
Data di deposito della tesi:30 November 2019
Anno di Pubblicazione:30 November 2019
Key Words:Parkinson's Disease, aSynuclein, Proteostasis, DOPAL
Settori scientifico-disciplinari MIUR:Area 05 - Scienze biologiche > BIO/09 Fisiologia
Struttura di riferimento:Centri > Centro Interdipartimentale di servizi A. Vallisneri
Dipartimenti > Dipartimento di Biologia
Codice ID:12170
Depositato il:25 Jan 2021 14:29
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