Harmol promotes α-synuclein degradation and improves motor impairment in Parkinson’s models via regulating autophagy-lysosome pathway

Xu, Jie; Ao, Yun-Lin; Huang, Cuiqing; Song, Xiubao; Zhang, Guiliang; Cui, Wei; Wang, Yuqiang; Zhang, Xiaoqi; Zhang, Zaijun

doi:10.1038/s41531-022-00361-4

Cited by 18 publications

(15 citation statements)

References 58 publications

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“…Inhibiting α-syn aggregation is an attractive target for combating α-syn-induced PD, and several groups have focused on the disaggregation of α-syn as a therapeutic mechanism [ 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 ], and these have been summarized and placed in ascending year of publication in Table 3 .…”

Section: Resultsmentioning

confidence: 99%

Are Therapies That Target α-Synuclein Effective at Halting Parkinson’s Disease Progression? A Systematic Review

Rodger

ALNasser

Carter

2023

IJMS

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There are currently no pharmacological treatments available that completely halt or reverse the progression of Parkinson’s Disease (PD). Hence, there is an unmet need for neuroprotective therapies. Lewy bodies are a neuropathological hallmark of PD and contain aggregated α-synuclein (α-syn) which is thought to be neurotoxic and therefore a suitable target for therapeutic interventions. To investigate this further, a systematic review was undertaken to evaluate whether anti-α-syn therapies are effective at preventing PD progression in preclinical in vivo models of PD and via current human clinical trials. An electronic literature search was performed using MEDLINE and EMBASE (Ovid), PubMed, the Web of Science Core Collection, and Cochrane databases to collate clinical evidence that investigated the targeting of α-syn. Novel preclinical anti-α-syn therapeutics provided a significant reduction of α-syn aggregations. Biochemical and immunohistochemical analysis of rodent brain tissue demonstrated that treatments reduced α-syn-associated pathology and rescued dopaminergic neuronal loss. Some of the clinical studies did not provide endpoints since they had not yet been completed or were terminated before completion. Completed clinical trials displayed significant tolerability and efficacy at reducing α-syn in patients with PD with minimal adverse effects. Collectively, this review highlights the capacity of anti-α-syn therapies to reduce the accumulation of α-syn in both preclinical and clinical trials. Hence, there is potential and optimism to target α-syn with further clinical trials to restrict dopaminergic neuronal loss and PD progression and/or provide prophylactic protection to avoid the onset of α-syn-induced PD.

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Section: Resultsmentioning

confidence: 99%

Are Therapies That Target α-Synuclein Effective at Halting Parkinson’s Disease Progression? A Systematic Review

Rodger

ALNasser

Carter

2023

IJMS

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“…Harmol has been reported to be an autophagy activator in a variety of disease models. For instance, harmol can activate the autophagy process by triggering extracellular signal-regulated kinase 1/2 (ERK1/2) and AMP-activated protein kinase [ 3 , 48 ]. Previous studies have reported that the activation of ERK or AMPK pathways were important for the host fighting against HSV infection [ 14 , 18 ].…”

Section: Discussionmentioning

confidence: 99%

Harmol used for the treatment of herpes simplex virus induced keratitis

Xu,

Zhou,

Huang

et al. 2024

Virol J

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Herpes simplex virus type 1 (HSV-1) infection of the eyes results in herpes simplex keratitis (HSK), which has led to vision loss and even blindness in patients. However, the rate of drug resistance in HSV is on the rise; therefore, new antiviral agents with sufficient safety profiles must be developed. At present, we assessed the anti-HSV-1 activity of 502 natural compounds and their ability to reduce the HSV-1-induced cytopathic effect. We chose harmol for further studies because it exhibited the highest antiviral activity. We found that harmol inhibited both HSV-1 F and HSV-1/153 (a clinical drug-resistant strain) replication, with an EC50 of 9.34 µM and 5.84 µM, respectively. Moreover, harmol reduced HSV-1 replication in corneal tissues and viral progeny production in tears, and also alleviated early corneal surface lesions related to HSK. For example, harmol treatment preserved corneal thickness and nerve density in HSK mice. Interestingly, harmol also showed a promising antiviral effect on HSV-1/153 induced HSK in mouse model. Furthermore, harmol combined with acyclovir (ACV) treatment showed a greater antiviral effect than either one alone in vitro. Therefore, harmol may be a promising therapeutic agent for managing HSK.

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“…Measuring the accumulation of different forms of α-synuclein is crucial in in vitro autophagy research of PD ( Guzzo et al, 2022 ). In this line, either monitoring of α-synuclein accumulation ( Xu et al, 2022 ) or exposing the cells to α-synuclein (e.g., oligomeric α-synuclein) ( Wang X. et al, 2020 ) to induce a pathological state are approaches used in PD research. Protein expression analysis by Western blot is commonly used to measure different forms of α-synuclein such as monomeric ( Alvarez-Erviti et al, 2013 ; di Domenico et al, 2019 ; Sackmann et al, 2019 ; Zeng et al, 2019 ; Sala et al, 2021 ; Mavroeidi et al, 2022 ), oligomeric ( Sala et al, 2021 ), and phosphorylated α-synuclein ( Xu et al, 2022 ).…”

Section: Parkinson’s Disease (Pd)mentioning

confidence: 99%

“…In this line, either monitoring of α-synuclein accumulation ( Xu et al, 2022 ) or exposing the cells to α-synuclein (e.g., oligomeric α-synuclein) ( Wang X. et al, 2020 ) to induce a pathological state are approaches used in PD research. Protein expression analysis by Western blot is commonly used to measure different forms of α-synuclein such as monomeric ( Alvarez-Erviti et al, 2013 ; di Domenico et al, 2019 ; Sackmann et al, 2019 ; Zeng et al, 2019 ; Sala et al, 2021 ; Mavroeidi et al, 2022 ), oligomeric ( Sala et al, 2021 ), and phosphorylated α-synuclein ( Xu et al, 2022 ). About 90% of the α-synuclein aggregates found in Lewy Bodies of brain tissue from PD patients are phosphorylated at serine 129 (Ser129-phosphorylated α-synuclein) ( Sasaki et al, 2015 ).…”

Section: Parkinson’s Disease (Pd)mentioning

confidence: 99%

“…Activators and inhibitors act at different stages of the autophagy pathway. Activators of the macroautophagy pathway include rapamycin ( Liu et al, 2019 ; Xu et al, 2022 ), AZD8055 ( Stathakos et al, 2021 ), and ambroxol ( Yang et al, 2017 ). Rapamycin is a drug that inhibits the mTOR signaling pathway, thus leading to the activation of the macroautophagy leading to a reduced accumulation of α-synuclein ( Moors et al, 2017 ).…”

Section: Parkinson’s Disease (Pd)mentioning

confidence: 99%

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In vitro methods in autophagy research: Applications in neurodegenerative diseases and mood disorders

Sánchez-Vidaña

Abokyi

et al. 2023

Front. Mol. Neurosci.

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BackgroundAutophagy is a conserved physiological intracellular mechanism responsible for the degradation and recycling of cytoplasmic constituents (e.g., damaged organelles, and protein aggregates) to maintain cell homeostasis. Aberrant autophagy has been observed in neurodegenerative diseases, including Alzheimer’s Disease (AD), Parkinson’s Disease (PD), Amyotrophic Lateral Sclerosis (ALS), and Huntington’s Disease (HD), and recently aberrant autophagy has been associated with mood disorders, such as depression. Several in vitro methods have been developed to study the complex and tightly regulated mechanisms of autophagy. In vitro methods applied to autophagy research are used to identify molecular key players involved in dysfunctional autophagy and to screen autophagy regulators with therapeutic applications in neurological diseases and mood disorders. Therefore, the aims of this narrative review are (1) to compile information on the cell-based methods used in autophagy research, (2) to discuss their application, and (3) to create a catalog of traditional and novel in vitro methods applied in neurodegenerative diseases and depression.MethodsPubmed and Google Scholar were used to retrieve relevant in vitro studies on autophagy mechanisms in neurological diseases and depression using a combination of search terms per mechanism and disease (e.g., “macroautophagy” and “Alzheimer’s disease”). A total of 37 studies were included (14 in PD, 8 in AD, 5 in ALS, 5 in %, and 5 in depression).ResultsA repertoire of traditional and novel approaches and techniques was compiled and discussed. The methods used in autophagy research focused on the mechanisms of macroautophagy, microautophagy, and chaperone-mediated autophagy. The in vitro tools presented in this review can be applied to explore pathophysiological mechanisms at a molecular level and to screen for potential therapeutic agents and their mechanism of action, which can be of great importance to understanding disease biology and potential therapeutic options in the context of neurodegenerative disorders and depression.ConclusionThis is the first review to compile, discuss, and provide a catalog of traditional and novel in vitro models applied to neurodegenerative disorders and depression.

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Harmol promotes α-synuclein degradation and improves motor impairment in Parkinson’s models via regulating autophagy-lysosome pathway

Cited by 18 publications

References 58 publications

Are Therapies That Target α-Synuclein Effective at Halting Parkinson’s Disease Progression? A Systematic Review

Are Therapies That Target α-Synuclein Effective at Halting Parkinson’s Disease Progression? A Systematic Review

Harmol used for the treatment of herpes simplex virus induced keratitis

In vitro methods in autophagy research: Applications in neurodegenerative diseases and mood disorders

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