Abstract:Parkinson's disease (PD) is the second most common neurodegenerative disorder in the aging population and is characterized by a constellation of motor and non-motor symptoms. The abnormal aggregation and spread of alpha-synuclein (α-syn) is thought to underlie the loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNc), leading to the development of PD. It is in this context that the use of adenoassociated viruses (AAVs) to express a-syn in the rodent midbrain has become a popular tool to… Show more
“…Modeling of CNS pathology has been pursued using different disease modeling strategies: (1) by artificial induction of dopamine deficit through delivery of a neurotoxin, (2) by viral-mediated local overexpression of asyn, (3) through induction of artificial asyn pathology by delivery of different aggregated forms of asyn (also called fibrils) in the brain, or (4) by using transgenic models characterized by elevated human asyn expression under specific promoters of wide or limited expression in the rodent (Dawson et al, 2018 ; Huntington and Srinivasan, 2021 ). CNS aggregate pathology has also been observed in other less common transgenic models, such as those that aim to induce PD by elimination of mitochondrial function (e.g., MitoPark) (Ekstrand and Galter, 2009 ).…”
Section: Impact Of Aging On Pathology and Neurodegenerationmentioning
confidence: 99%
“…Importantly, differences in CNS-sensitivity to a neurotoxin (Song et al, 2015 ) or viral-mediated mediated overexpression of asyn (Huntington and Srinivasan, 2021 ) have been observed across different strains, even when not genetically engineered, and these differences might be magnified when working with aged animals. More studies in different strains need to be done to assess the effect of aging on multiple features of PD pathogenesis.…”
Section: Impact Of Aging On Pathology and Neurodegenerationmentioning
Aging is the biggest risk factor for developing Parkinson's disease (PD), the second most common neurodegenerative disorder. Several animal models have been developed to explore the pathophysiology underlying neurodegeneration and the initiation and spread of alpha-synuclein-related PD pathology, and to investigate biomarkers and therapeutic strategies. However, bench-to-bedside translation of preclinical findings remains suboptimal and successful disease-modifying treatments remain to be discovered. Despite aging being the main risk factor for developing idiopathic PD, most studies employ young animals in their experimental set-up, hereby ignoring age-related cellular and molecular mechanisms at play. Consequently, studies in young animals may not be an accurate reflection of human PD, limiting translational outcomes. Recently, it has been shown that aged animals in PD research demonstrate a higher susceptibility to developing pathology and neurodegeneration, and present with a more disseminated and accelerated disease course, compared to young animals. Here we review recent advances in the investigation of the role of aging in preclinical PD research, including challenges related to aged animal models that are limiting widespread use. Overall, current findings indicate that the use of aged animals may be required to account for age-related interactions in PD pathophysiology. Thus, although the use of older animals has disadvantages, a model that better represents clinical disease within the elderly would be more beneficial in the long run, as it will increase translational value and minimize the risk of therapies failing during clinical studies. Furthermore, we provide recommendations to manage the challenges related to aged animal models.
“…Modeling of CNS pathology has been pursued using different disease modeling strategies: (1) by artificial induction of dopamine deficit through delivery of a neurotoxin, (2) by viral-mediated local overexpression of asyn, (3) through induction of artificial asyn pathology by delivery of different aggregated forms of asyn (also called fibrils) in the brain, or (4) by using transgenic models characterized by elevated human asyn expression under specific promoters of wide or limited expression in the rodent (Dawson et al, 2018 ; Huntington and Srinivasan, 2021 ). CNS aggregate pathology has also been observed in other less common transgenic models, such as those that aim to induce PD by elimination of mitochondrial function (e.g., MitoPark) (Ekstrand and Galter, 2009 ).…”
Section: Impact Of Aging On Pathology and Neurodegenerationmentioning
confidence: 99%
“…Importantly, differences in CNS-sensitivity to a neurotoxin (Song et al, 2015 ) or viral-mediated mediated overexpression of asyn (Huntington and Srinivasan, 2021 ) have been observed across different strains, even when not genetically engineered, and these differences might be magnified when working with aged animals. More studies in different strains need to be done to assess the effect of aging on multiple features of PD pathogenesis.…”
Section: Impact Of Aging On Pathology and Neurodegenerationmentioning
Aging is the biggest risk factor for developing Parkinson's disease (PD), the second most common neurodegenerative disorder. Several animal models have been developed to explore the pathophysiology underlying neurodegeneration and the initiation and spread of alpha-synuclein-related PD pathology, and to investigate biomarkers and therapeutic strategies. However, bench-to-bedside translation of preclinical findings remains suboptimal and successful disease-modifying treatments remain to be discovered. Despite aging being the main risk factor for developing idiopathic PD, most studies employ young animals in their experimental set-up, hereby ignoring age-related cellular and molecular mechanisms at play. Consequently, studies in young animals may not be an accurate reflection of human PD, limiting translational outcomes. Recently, it has been shown that aged animals in PD research demonstrate a higher susceptibility to developing pathology and neurodegeneration, and present with a more disseminated and accelerated disease course, compared to young animals. Here we review recent advances in the investigation of the role of aging in preclinical PD research, including challenges related to aged animal models that are limiting widespread use. Overall, current findings indicate that the use of aged animals may be required to account for age-related interactions in PD pathophysiology. Thus, although the use of older animals has disadvantages, a model that better represents clinical disease within the elderly would be more beneficial in the long run, as it will increase translational value and minimize the risk of therapies failing during clinical studies. Furthermore, we provide recommendations to manage the challenges related to aged animal models.
“…Transgene delivery using viral vectors has become an alternative approach for creating models for human diseases in rats, pigs, and non-human primates. Among other viruses, AAV vectors have proven to be an ideal tool for modeling severe neurological and neuromuscular disorders due to high tropism to neuronal tissues, skeletal and cardiac muscles (Duque et al 2015;Huntington and Srinivasan 2021).…”
Disease-causing genes have been identified for many severe muscular and neurological genetic disorders. Advances in the gene therapy field offer promising solutions for drug development to treat these life-threatening conditions. Depending on how the mutation affects the function of the gene product, different gene therapy approaches may be beneficial. Gene replacement therapy is appropriate for diseases caused by mutations that result in the deficiency of the functional protein. Gene suppression strategy is suggested for disorders caused by the toxic product of the mutant gene. Splicing modulators, genome editing, and base editing techniques can be applied to disorders with different types of underlying mutations. Testing potential drugs in animal models of human diseases is an indispensable step of development. Given the specific gene therapy approach, appropriate animal models can be generated using a variety of technologies ranging from transgenesis to precise genome editing. In this review, we discuss technologies used to generate small and large animal models of the most common muscular and neurological genetic disorders. We specifically focus on animal models that were used to test gene therapies based on adeno-associated vectors and antisense nucleotides.
“…Astrocytes also possess a plethora of spontaneous Ca ++ signals that regulate diverse signaling pathways that could act in an autocrine manner to modulate nearby cells [ 134 , 135 ]. In addition, increased levels of Ca ++ ER and altered mitochondrial functions are described in PD patients, which, in turn, will worsen the redox status, thus impairing the antioxidant support and lactate shuttle to neurons.…”
Section: Evidence For Astrocyte Roles In Pd As a Non-neuronal Cell Au...mentioning
Parkinson’s disease (PD) is an incurable neurodegenerative disease of high prevalence, characterized by the prominent death of dopaminergic neurons in the substantia nigra pars compacta, which produces dopamine deficiency, leading to classic motor symptoms. Although PD has traditionally been considered as a neuronal cell autonomous pathology, in which the damage of vulnerable neurons is responsible for the disease, growing evidence strongly suggests that astrocytes might have an active role in the neurodegeneration observed. In the present review, we discuss several studies evidencing astrocyte implications in PD, highlighting the consequences of both the loss of normal homeostatic functions and the gain in toxic functions for the wellbeing of dopaminergic neurons. The revised information provides significant evidence that allows astrocytes to be positioned as crucial players in PD etiology, a factor that needs to be taken into account when considering therapeutic targets for the treatment of the disease.
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