LRRK2: Genetic mechanisms vs genetic subtypes

Mata, Ignacio; Salles, Philippe A.; Cornejo‐Olivas, Mario; Awad, Paula Saffie; Ross, Owen A.; Reed, Xylena; Bandrés‐Ciga, Sara

doi:10.1016/b978-0-323-85555-6.00018-7

Cited by 6 publications

(2 citation statements)

References 202 publications

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“…Also, the genetic expression and splicing events can differ between human and animal models [28]. Critically, different variants within the same gene (see LRRK2) are associated with several different types of parkinsonian syndromes [29].…”

Section: Pros and Cons Of Available Animal Modelsmentioning

confidence: 99%

Recalibrating the Why and Whom of Animal Models in Parkinson Disease: A Clinician’s Perspective

Sturchio,

Rocha,

Kauffman

et al. 2024

Brain Sciences

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Animal models have been used to gain pathophysiologic insights into Parkinson’s disease (PD) and aid in the translational efforts of interventions with therapeutic potential in human clinical trials. However, no disease-modifying therapy for PD has successfully emerged from model predictions. These translational disappointments warrant a reappraisal of the types of preclinical questions asked of animal models. Besides the limitations of experimental designs, the one-size convergence and oversimplification yielded by a model cannot recapitulate the molecular diversity within and between PD patients. Here, we compare the strengths and pitfalls of different models, review the discrepancies between animal and human data on similar pathologic and molecular mechanisms, assess the potential of organoids as novel modeling tools, and evaluate the types of questions for which models can guide and misguide. We propose that animal models may be of greatest utility in the evaluation of molecular mechanisms, neural pathways, drug toxicity, and safety but can be unreliable or misleading when used to generate pathophysiologic hypotheses or predict therapeutic efficacy for compounds with potential neuroprotective effects in humans. To enhance the translational disease-modification potential, the modeling must reflect the biology not of a diseased population but of subtypes of diseased humans to distinguish What data are relevant and to Whom.

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Section: Pros and Cons Of Available Animal Modelsmentioning

confidence: 99%

Recalibrating the Why and Whom of Animal Models in Parkinson Disease: A Clinician’s Perspective

Sturchio,

Rocha,

Kauffman

et al. 2024

Brain Sciences

View full text Add to dashboard Cite

show abstract

“…Some common mutations in the gene coding for leucine-rich repeat kinase 2 (LRRK2) have been linked to early-onset familial and late-onset sporadic PD, and the protein is considered an attractive target for immunotherapy of the disease [ 67 – 70 ]. This enzyme has two catalytic activities: GTPase activity mediated by the Roc domain and Ser/Thr protein kinase activity [ 71 ].…”

Section: Recombinant Antibody Fragmentsmentioning

confidence: 99%

Recombinant Antibody Fragments for Immunotherapy of Parkinson’s Disease

Manoutcharian,

Gevorkian

2024

BioDrugs

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Parkinson’s disease (PD) is the second most common age-related neurodegenerative disorder. Multiple genetic and environmental factors leading to progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SN) and consequent depletion of dopamine were described. Current clinical approaches, such as dopamine replacement or deep brain stimulation using surgically implanted probes, provide symptomatic relief but cannot modify disease progression. Therefore, disease-modifying therapeutic tools are urgently needed. Immunotherapy approaches, including passive transfer of protective antibodies and their fragments, have shown therapeutic efficacy in several animal models of neurodegenerative diseases, including PD. Recombinant antibody fragments are promising alternatives to conventional full-length antibodies. Modern computational approaches and molecular biology tools, directed evolution methodology, and the design of tissue-penetrating fusion peptides allowed for the development of recombinant antibody fragments with superior specificity and affinity, reduced immunogenicity, the capacity to target hidden epitopes and cross the blood-brain barrier (BBB), higher solubility and stability, the ability to refold after heat denaturation, and inexpensive large-scale production. In addition, antibody fragments do not induce microglia Fcγ receptor (FcγR)-mediated proinflammatory response and tissue damage in the central nervous system (CNS), because they lack the Fc portion of the immunoglobulin molecule. In the present review, we summarized data on recombinant antibody fragments evaluated as immunotherapeutics in preclinical models of PD and discussed their potential for developing therapeutic and preventive protocols for patients with PD.

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