LRRK2 and Protein Aggregation in Parkinson’s Disease: Insights From Animal Models

Dues, Dylan J.; Moore, Darren J.

doi:10.3389/fnins.2020.00719

Cited by 13 publications

(13 citation statements)

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“…Up to the present study, pomalidomide has not been evaluated in mammalian models of PD. In a recent study, we reported its efficacy in a Drosophila LRRK2 WD40 genetic PD model [16,65]. In that study, we showed that LRRK2 WD40 flies develop motor impairment and gradual loss of dopaminergic neurons with age [16], and pomalidomide administration through the diet prevented both age-dependent motor impairment and neuronal loss [16].…”

Section: Discussionmentioning

confidence: 98%

Repurposing Pomalidomide as a Neuroprotective Drug: Efficacy in an Alpha-Synuclein-Based Model of Parkinson's Disease

et al. 2022

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Marketed drugs for Parkinson’s disease (PD) treat disease motor symptoms but are ineffective in stopping or slowing disease progression. In the quest of novel pharmacological approaches that may target disease progression, drug-repurposing provides a strategy to accelerate the preclinical and clinical testing of drugs already approved for other medical indications. Here, we targeted the inflammatory component of PD pathology, by testing for the first time the disease-modifying properties of the immunomodulatory imide drug (IMiD) pomalidomide in a translational rat model of PD neuropathology based on the intranigral bilateral infusion of toxic preformed oligomers of human α-synuclein (H-αSynOs). The neuroprotective effect of pomalidomide (20 mg/kg; i.p. three times/week 48 h apart) was tested in the first stage of disease progression by means of a chronic two-month administration, starting 1 month after H-αSynOs infusion, when an already ongoing neuroinflammation is observed. The intracerebral infusion of H-αSynOs induced an impairment in motor and coordination performance that was fully rescued by pomalidomide, as assessed via a battery of motor tests three months after infusion. Moreover, H-αSynOs-infused rats displayed a 40–45% cell loss within the bilateral substantia nigra, as measured by stereological counting of TH + and Nissl-stained neurons, that was largely abolished by pomalidomide. The inflammatory response to H-αSynOs infusion and the pomalidomide treatment was evaluated both in CNS affected areas and peripherally in the serum. A reactive microgliosis, measured as the volume occupied by the microglial marker Iba-1, was present in the substantia nigra three months after H-αSynOs infusion as well as after H-αSynOs plus pomalidomide treatment. However, microglia differed for their phenotype among experimental groups. After H-αSynOs infusion, microglia displayed a proinflammatory profile, producing a large amount of the proinflammatory cytokine TNF-α. In contrast, pomalidomide inhibited the TNF-α overproduction and elevated the anti-inflammatory cytokine IL-10. Moreover, the H-αSynOs infusion induced a systemic inflammation with overproduction of serum proinflammatory cytokines and chemokines, that was largely mitigated by pomalidomide. Results provide evidence of the disease modifying potential of pomalidomide in a neuropathological rodent model of PD and support the repurposing of this drug for clinical testing in PD patients.

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Section: Discussionmentioning

confidence: 98%

Repurposing Pomalidomide as a Neuroprotective Drug: Efficacy in an Alpha-Synuclein-Based Model of Parkinson's Disease

et al. 2022

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“…Interestingly, IMiDs decreased the α-Syn-induced inflammatory response also in non-motor regions of the brain such as the hippocampus, an area involved in cognitive deficits of PD, supporting a role of neuroinflammation in these non-motor symptoms ( Valera et al, 2015 ; Williams-Gray et al, 2016 ). A recent study demonstrated the pomalidomide efficacy in a drosophila LRRK2 WD40 mutant PD model, with LRRK2 being a common genetic cause of PD ( Casu et al, 2020 ; Dues and Moore, 2020 ). These flies develop motor impairment and gradually lose dopaminergic neurons with age ( Casu et al, 2020 ).…”

Section: Imids and Neurodegenerative Disorders: Preclinical And Clinical Evidencementioning

confidence: 99%

Repurposing Immunomodulatory Imide Drugs (IMiDs) in Neuropsychiatric and Neurodegenerative Disorders

et al. 2021

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Neuroinflammation represents a common trait in the pathology and progression of the major psychiatric and neurodegenerative disorders. Neuropsychiatric disorders have emerged as a global crisis, affecting 1 in 4 people, while neurological disorders are the second leading cause of death in the elderly population worldwide (WHO, 2001; GBD 2016 Neurology Collaborators, 2019). However, there remains an immense deficit in availability of effective drug treatments for most neurological disorders. In fact, for disorders such as depression, placebos and behavioral therapies have equal effectiveness as antidepressants. For neurodegenerative diseases such as Parkinson’s disease and Alzheimer’s disease, drugs that can prevent, slow, or cure the disease have yet to be found. Several non-traditional avenues of drug target identification have emerged with ongoing neurological disease research to meet the need for novel and efficacious treatments. Of these novel avenues is that of neuroinflammation, which has been found to be involved in the progression and pathology of many of the leading neurological disorders. Neuroinflammation is characterized by glial inflammatory factors in certain stages of neurological disorders. Although the meta-analyses have provided evidence of genetic/proteomic upregulation of inflammatory factors in certain stages of neurological disorders. Although the mechanisms underpinning the connections between neuroinflammation and neurological disorders are unclear, and meta-analysis results have shown high sensitivity to factors such as disorder severity and sample type, there is significant evidence of neuroinflammation associations across neurological disorders. In this review, we summarize the role of neuroinflammation in psychiatric disorders such as major depressive disorder, generalized anxiety disorder, post-traumatic stress disorder, and bipolar disorder, as well as in neurodegenerative disorders, such as Parkinson’s disease and Alzheimer’s disease, and introduce current research on the potential of immunomodulatory imide drugs (IMiDs) as a new treatment strategy for these disorders.

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“…Considered to be second most persisting/recurring ND worldwide with multifaceted etiologies, Parkinson’s disease affects approximately 1–2% of the population [ 18 , 19 ]. An intra-neuronal buildup of protein aggregates and Lewy bodies (consisting of misfolded α-synuclein) and gradual decline of dopaminergic neurons in the substantia nigra pars compacta [ 20 , 21 ] are the two major neuropathological processes involved in Parkinson’s disease. Patients with Parkinson’s suffer from a variety of non-motor symptoms, uncontrollable tremors, and diminished motor function that exacerbate in the later stages of the disease [ 22 , 23 ].…”

Section: Brief Overview Of Neurodegenerative Diseases (Nds)mentioning

confidence: 99%

“…Huntington’s disease is an inherited ND characterized pathologically by diminished functions of gamma-aminobutyric acid and excessive dopaminergic activity in the basal ganglia. Clinically, it is characterized by psychiatric disturbance, abnormal movements, and cognitive deficits [ 21 ], being associated with the expansion of the trinucleotide repeat in the Huntington (Htt) gene present at the short arm of chromosome 4. Htt (mutant) proteolysis has been observed to contribute to its pathology, but its role is not yet well defined [ 39 ].…”

Section: Brief Overview Of Neurodegenerative Diseases (Nds)mentioning

confidence: 99%

Elucidating the Multi-Targeted Role of Nutraceuticals: A Complementary Therapy to Starve Neurodegenerative Diseases

Behl

Kaur

Sehgal

et al. 2021

IJMS

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The mechanisms underlying multifactorial diseases are always complex and challenging. Neurodegenerative disorders (NDs) are common around the globe, posing a critical healthcare issue and financial burden to the country. However, integrative evidence implies some common shared mechanisms and pathways in NDs, which include mitochondrial dysfunction, neuroinflammation, oxidative stress, intracellular calcium overload, protein aggregates, oxidative stress (OS), and neuronal destruction in specific regions of the brain, owing to multifaceted pathologies. The co-existence of these multiple pathways often limits the advantages of available therapies. The nutraceutical-based approach has opened the doors to target these common multifaceted pathways in a slow and more physiological manner to starve the NDs. Peer-reviewed articles were searched via MEDLINE and PubMed published to date for in-depth research and database collection. Considered to be complementary therapy with current clinical management and common drug therapy, the intake of nutraceuticals is considered safe to target multiple mechanisms of action in NDs. The current review summarizes the popular nutraceuticals showing different effects (anti-inflammatory, antioxidant, neuro-protectant, mitochondrial homeostasis, neurogenesis promotion, and autophagy regulation) on vital molecular mechanisms involved in NDs, which can be considered as complementary therapy to first-line treatment. Moreover, owing to its natural source, lower toxicity, therapeutic interventions, biocompatibility, potential nutritional effects, and presence of various anti-oxidative and neuroprotective constituents, the nutraceuticals serve as an attractive option to tackle NDs.

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LRRK2 and Protein Aggregation in Parkinson’s Disease: Insights From Animal Models

Cited by 13 publications

References 93 publications

Repurposing Pomalidomide as a Neuroprotective Drug: Efficacy in an Alpha-Synuclein-Based Model of Parkinson's Disease

Repurposing Pomalidomide as a Neuroprotective Drug: Efficacy in an Alpha-Synuclein-Based Model of Parkinson's Disease

Repurposing Immunomodulatory Imide Drugs (IMiDs) in Neuropsychiatric and Neurodegenerative Disorders

Elucidating the Multi-Targeted Role of Nutraceuticals: A Complementary Therapy to Starve Neurodegenerative Diseases

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