Roles of neuronal lysosomes in the etiology of Parkinson's disease
Therapeutic progress in neurodegenerative conditions such as Parkinson's disease has been hampered by a lack of detailed knowledge of its molecular etiology. The advancements in genetics and genomics have provided fundamental insights into specific protein players and the cellular processes inv...
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| Format: | Article |
| Language: | English |
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Wolters Kluwer Medknow Publications
2024-01-01
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| Series: | Neural Regeneration Research |
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| Online Access: | http://www.nrronline.org/article.asp?issn=1673-5374;year=2024;volume=19;issue=9;spage=1981;epage=1983;aulast= |
| _version_ | 1797299960731926528 |
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| author | Mattia Volta |
| author_facet | Mattia Volta |
| author_sort | Mattia Volta |
| collection | DOAJ |
| description | Therapeutic progress in neurodegenerative conditions such as Parkinson's disease has been hampered by a lack of detailed knowledge of its molecular etiology. The advancements in genetics and genomics have provided fundamental insights into specific protein players and the cellular processes involved in the onset of disease. In this respect, the autophagy-lysosome system has emerged in recent years as a strong point of convergence for genetics, genomics, and pathologic indications, spanning both familial and idiopathic Parkinson's disease. Most, if not all, genes linked to familial disease are involved, in a regulatory capacity, in lysosome function (e.g., LRRK2, alpha-synuclein, VPS35, Parkin, and PINK1). Moreover, the majority of genomic loci associated with increased risk of idiopathic Parkinson's cluster in lysosome biology and regulation (GBA as the prime example). Lastly, neuropathologic evidence showed alterations in lysosome markers in autoptic material that, coupled to the alpha-synuclein proteinopathy that defines the disease, strongly indicate an alteration in functionality. In this Brief Review article, I present a personal perspective on the molecular and cellular involvement of lysosome biology in Parkinson's pathogenesis, aiming at a larger vision on the events underlying the onset of the disease. The attempts at targeting autophagy for therapeutic purposes in Parkinson's have been mostly aimed at “indiscriminately” enhancing its activity to promote the degradation and elimination of aggregate protein accumulations, such as alpha-synuclein Lewy bodies. However, this approach is based on the assumption that protein pathology is the root cause of disease, while pre-pathology and pre-degeneration dysfunctions have been largely observed in clinical and pre-clinical settings. In addition, it has been reported that unspecific boosting of autophagy can be detrimental. Thus, it is important to understand the mechanisms of specific autophagy forms and, even more, the adjustment of specific lysosome functionalities. Indeed, lysosomes exert fine signaling capacities in addition to their catabolic roles and might participate in the regulation of neuronal and glial cell functions. Here, I discuss hypotheses on these possible mechanisms, their links with etiologic and risk factors for Parkinson's disease, and how they could be targeted for disease-modifying purposes. |
| first_indexed | 2024-03-07T22:59:15Z |
| format | Article |
| id | doaj.art-8268d14dfdc149f1a8a8491a4fb78657 |
| institution | Directory Open Access Journal |
| issn | 1673-5374 |
| language | English |
| last_indexed | 2024-03-07T22:59:15Z |
| publishDate | 2024-01-01 |
| publisher | Wolters Kluwer Medknow Publications |
| record_format | Article |
| series | Neural Regeneration Research |
| spelling | doaj.art-8268d14dfdc149f1a8a8491a4fb786572024-02-22T15:19:04ZengWolters Kluwer Medknow PublicationsNeural Regeneration Research1673-53742024-01-011991981198310.4103/1673-5374.390954Roles of neuronal lysosomes in the etiology of Parkinson's diseaseMattia VoltaTherapeutic progress in neurodegenerative conditions such as Parkinson's disease has been hampered by a lack of detailed knowledge of its molecular etiology. The advancements in genetics and genomics have provided fundamental insights into specific protein players and the cellular processes involved in the onset of disease. In this respect, the autophagy-lysosome system has emerged in recent years as a strong point of convergence for genetics, genomics, and pathologic indications, spanning both familial and idiopathic Parkinson's disease. Most, if not all, genes linked to familial disease are involved, in a regulatory capacity, in lysosome function (e.g., LRRK2, alpha-synuclein, VPS35, Parkin, and PINK1). Moreover, the majority of genomic loci associated with increased risk of idiopathic Parkinson's cluster in lysosome biology and regulation (GBA as the prime example). Lastly, neuropathologic evidence showed alterations in lysosome markers in autoptic material that, coupled to the alpha-synuclein proteinopathy that defines the disease, strongly indicate an alteration in functionality. In this Brief Review article, I present a personal perspective on the molecular and cellular involvement of lysosome biology in Parkinson's pathogenesis, aiming at a larger vision on the events underlying the onset of the disease. The attempts at targeting autophagy for therapeutic purposes in Parkinson's have been mostly aimed at “indiscriminately” enhancing its activity to promote the degradation and elimination of aggregate protein accumulations, such as alpha-synuclein Lewy bodies. However, this approach is based on the assumption that protein pathology is the root cause of disease, while pre-pathology and pre-degeneration dysfunctions have been largely observed in clinical and pre-clinical settings. In addition, it has been reported that unspecific boosting of autophagy can be detrimental. Thus, it is important to understand the mechanisms of specific autophagy forms and, even more, the adjustment of specific lysosome functionalities. Indeed, lysosomes exert fine signaling capacities in addition to their catabolic roles and might participate in the regulation of neuronal and glial cell functions. Here, I discuss hypotheses on these possible mechanisms, their links with etiologic and risk factors for Parkinson's disease, and how they could be targeted for disease-modifying purposes.http://www.nrronline.org/article.asp?issn=1673-5374;year=2024;volume=19;issue=9;spage=1981;epage=1983;aulast=alpha-synuclein; autophagy; lrrk2; lysosome; neuroprotection; neurotransmission; parkinson's disease; rit2; synapse |
| spellingShingle | Mattia Volta Roles of neuronal lysosomes in the etiology of Parkinson's disease Neural Regeneration Research alpha-synuclein; autophagy; lrrk2; lysosome; neuroprotection; neurotransmission; parkinson's disease; rit2; synapse |
| title | Roles of neuronal lysosomes in the etiology of Parkinson's disease |
| title_full | Roles of neuronal lysosomes in the etiology of Parkinson's disease |
| title_fullStr | Roles of neuronal lysosomes in the etiology of Parkinson's disease |
| title_full_unstemmed | Roles of neuronal lysosomes in the etiology of Parkinson's disease |
| title_short | Roles of neuronal lysosomes in the etiology of Parkinson's disease |
| title_sort | roles of neuronal lysosomes in the etiology of parkinson s disease |
| topic | alpha-synuclein; autophagy; lrrk2; lysosome; neuroprotection; neurotransmission; parkinson's disease; rit2; synapse |
| url | http://www.nrronline.org/article.asp?issn=1673-5374;year=2024;volume=19;issue=9;spage=1981;epage=1983;aulast= |
| work_keys_str_mv | AT mattiavolta rolesofneuronallysosomesintheetiologyofparkinsonsdisease |