LRRK2 and Proteostasis in Parkinson’s Disease

Pérez-Carrión, María Dolores; Posadas, Inmaculada; Solera, Javier; Ceña, Valentı́n

doi:10.3390/ijms23126808

Cited by 10 publications

(7 citation statements)

References 206 publications

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“…It is also important to mention the role of leucine-rich repeat kinase 2 (LRRK2), as the hyperactivity of this kinase and the presence of mutations in it have been associated with an increased risk of PD. For this reason, the study of LRRK2 inhibition as a potential treatment has been proposed [ 130 ]. One of the LRRK2 inhibitors recently studied in Phase I and Ib clinical trials is DNL201.…”

Section: Resultsmentioning

confidence: 99%

Current Treatments and New, Tentative Therapies for Parkinson’s Disease

Pardo-Moreno¹,

García‐Morales

Suleiman‐Martos

et al. 2023

Pharmaceutics

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Parkinson’s disease (PD) is a neurodegenerative pathology, the origin of which is associated with the death of neuronal cells involved in the production of dopamine. The prevalence of PD has increased exponentially. The aim of this review was to describe the novel treatments for PD that are currently under investigation and study and the possible therapeutic targets. The pathophysiology of this disease is based on the formation of alpha-synuclein folds that generate Lewy bodies, which are cytotoxic and reduce dopamine levels. Most pharmacological treatments for PD target alpha-synuclein to reduce the symptoms. These include treatments aimed at reducing the accumulation of alpha-synuclein (epigallocatechin), reducing its clearance via immunotherapy, inhibiting LRRK2, and upregulating cerebrosidase (ambroxol). Parkinson’s disease continues to be a pathology of unknown origin that generates a significant social cost for the patients who suffer from it. Although there is still no definitive cure for this disease at present, there are numerous treatments available aimed at reducing the symptomatology of PD in addition to other therapeutic alternatives that are still under investigation. However, the therapeutic approach to this pathology should include a combination of pharmacological and non-pharmacological strategies to maximise outcomes and improve symptomatological control in these patients. It is therefore necessary to delve deeper into the pathophysiology of the disease in order to improve these treatments and therefore the quality of life of the patients.

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Section: Resultsmentioning

confidence: 99%

Current Treatments and New, Tentative Therapies for Parkinson’s Disease

Pardo-Moreno¹,

García‐Morales

Suleiman‐Martos

et al. 2023

Pharmaceutics

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“…Of these proteins, LRRK2 stands out as being particularly prevalent, being one of the more frequently mutated genes associated with the condition-LRRK2 contains both GTPase domains; mutations are present both with autosomal dominant Parkinsonism as well as being linked with its development sporadically; its mutation rate accounts for around one percent and five percent in relation to familial Parkinsonism, respectively, making LRRK2 one of its more prominent genetic contributors to its association with Parkinsonism. LRRK2 plays an essential role in the GA [110][111][112][113]. LRRK2 mutants disrupt its integrity and vesicle trafficking.…”

Section: Golgi Apparatus-parkinsonmentioning

confidence: 99%

The Golgi Apparatus: A Voyage through Time, Structure, Function and Implication in Neurodegenerative Disorders

Mohan,

Calenic,

Ghiurau

et al. 2023

Cells

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This comprehensive review article dives deep into the Golgi apparatus, an essential organelle in cellular biology. Beginning with its discovery during the 19th century until today’s recognition as an important contributor to cell function. We explore its unique organization and structure as well as its roles in protein processing, sorting, and lipid biogenesis, which play key roles in maintaining homeostasis in cellular biology. This article further explores Golgi biogenesis, exploring its intricate processes and dynamics that contribute to its formation and function. One key focus is its role in neurodegenerative diseases like Parkinson’s, where changes to the structure or function of the Golgi apparatus may lead to their onset or progression, emphasizing its key importance in neuronal health. At the same time, we examine the intriguing relationship between Golgi stress and endoplasmic reticulum (ER) stress, providing insights into their interplay as two major cellular stress response pathways. Such interdependence provides a greater understanding of cellular reactions to protein misfolding and accumulation, hallmark features of many neurodegenerative diseases. In summary, this review offers an exhaustive examination of the Golgi apparatus, from its historical background to its role in health and disease. Additionally, this examination emphasizes the necessity of further research in this field in order to develop targeted therapeutic approaches for Golgi dysfunction-associated conditions. Furthermore, its exploration is an example of scientific progress while simultaneously offering hope for developing innovative treatments for neurodegenerative disorders.

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“…This includes proteostasis [13], whose alteration is often linked to various neurodegenerative diseases. In recent years, numerous studies have been conducted in this direction to elucidate the actual interplay between proteostasis and PD [14,15]. To gain deeper insights into this process, the current study aimed to investigate the dysregulation of elements involved in the proteostasis-related mechanism at the transcriptomic level.…”

Section: Introductionmentioning

confidence: 99%

Network Analysis Performed on Transcriptomes of Parkinson’s Disease Patients Reveals Dysfunction in Protein Translation

D’Angiolini,

Lui,

Mazzon

et al. 2024

IJMS

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Parkinson’s disease (PD) is a prevalent neurodegenerative disorder characterized by the progressive degeneration of dopaminergic neurons in the substantia nigra region of the brain. The hallmark pathological feature of PD is the accumulation of misfolded proteins, leading to the formation of intracellular aggregates known as Lewy bodies. Recent data evidenced how disruptions in protein synthesis, folding, and degradation are events commonly observed in PD and may provide information on the molecular background behind its etiopathogenesis. In the present study, we used a publicly available transcriptomic microarray dataset of peripheral blood of PD patients and healthy controls (GSE6613) to investigate the potential dysregulation of elements involved in proteostasis-related processes at the transcriptomic level. Our bioinformatics analysis revealed 375 differentially expressed genes (DEGs), of which 281 were down-regulated and 94 were up-regulated. Network analysis performed on the observed DEGs highlighted a cluster of 36 elements mainly involved in the protein synthesis processes. Different enriched ontologies were related to translation initiation and regulation, ribosome structure, and ribosome components nuclear export. Overall, this data consistently points to a generalized impairment of the translational machinery and proteostasis. Dysregulation of these mechanics has been associated with PD pathogenesis. Understanding the precise regulation of such processes may shed light on the molecular mechanisms of PD and provide potential data for early diagnosis.

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LRRK2 and Proteostasis in Parkinson’s Disease

Cited by 10 publications

References 206 publications

Current Treatments and New, Tentative Therapies for Parkinson’s Disease

Current Treatments and New, Tentative Therapies for Parkinson’s Disease

The Golgi Apparatus: A Voyage through Time, Structure, Function and Implication in Neurodegenerative Disorders

Network Analysis Performed on Transcriptomes of Parkinson’s Disease Patients Reveals Dysfunction in Protein Translation

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