Calpains as mechanistic drivers and therapeutic targets for ocular disease

Vu, Jennifer; Wang, Elena; Wu, Jolan; Sun, Young Joo; Vélez, Gabriel; Bassuk, Alexander G.; Lee, Soo Hyun; Mahajan, Vinit B.

doi:10.1016/j.molmed.2022.05.007

Cited by 8 publications

(2 citation statements)

References 151 publications

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“…Calpain-2 could become hyperactive in the later stages of neurodegenerative diseases such as AD. This hyperactivity may increase beta-amyloid deposits, which can lead to further cognitive decline [130,131]. Overall, calpain-1 and calpain-2 play important roles in organizing neurotransmitter receptors, releasing neurotransmitters, regulating cytoskeletal dynamics, and facilitating local protein translation [27,[132][133][134].…”

Section: Calpain's Role In Neuroinflammation and Pdmentioning

confidence: 99%

Insights into Calpain Activation and Rho-ROCK Signaling in Parkinson’s Disease and Aging

Gathings,

Zaman,

Banik

et al. 2024

Biomedicines

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Parkinson’s disease (PD), a progressive neurodegenerative disease, has no cure, and current therapies are not effective at halting disease progression. The disease affects mid-brain dopaminergic neurons and, subsequently, the spinal cord, contributing to many debilitating symptoms associated with PD. The GTP-binding protein, Rho, plays a significant role in the cellular pathology of PD. The downstream effector of Rho, Rho-associated kinase (ROCK), plays multiple functions, including microglial activation and induction of inflammatory responses. Activated microglia have been implicated in the pathology of many neurodegenerative diseases, including PD, that initiate inflammatory responses, leading to neuron death. Calpain expression and activity is increased following glial activation, which triggers the Rho-ROCK pathway and induces inflammatory T cell activation and migration as well as mediates toxic α-synuclein (α-syn) aggregation and neuron death, indicating a pivotal role for calpain in the inflammatory and degenerative processes in PD. Increased calpain activity and Rho-ROCK activation may represent a new mechanism for increased oxidative damage in aging. This review will summarize calpain activation and the role of the Rho-ROCK pathway in oxidative stress and α-syn aggregation, their influence on the neurodegenerative process in PD and aging, and possible strategies and research directions for therapeutic intervention.

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Section: Calpain's Role In Neuroinflammation and Pdmentioning

confidence: 99%

Insights into Calpain Activation and Rho-ROCK Signaling in Parkinson’s Disease and Aging

Gathings,

Zaman,

Banik

et al. 2024

Biomedicines

View full text Add to dashboard Cite

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“…Activated calpains then cleave a variety of cytoplasmic and nuclear substrates, including caspase 3 and PARP [ 146 , 147 ]. The activation of calpains also induces the release of AIF from mitochondria, leading to prolonged proteolysis and apoptosis/necroptosis [ 114 , 139 , 148 , 149 , 150 , 151 , 152 ]. Retinas of rd1 and rd10 mice show increased calpain activity, which peaks synchronously with cell death [ 139 , 148 , 150 , 152 ].…”

Section: The Cellular and Molecular Mechanisms Underlying Cgmp Signal...mentioning

confidence: 99%

cGMP Signaling in Photoreceptor Degeneration

Yang

et al. 2023

IJMS

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Photoreceptors in the retina are highly specialized neurons with photosensitive molecules in the outer segment that transform light into chemical and electrical signals, and these signals are ultimately relayed to the visual cortex in the brain to form vision. Photoreceptors are composed of rods and cones. Rods are responsible for dim light vision, whereas cones are responsible for bright light, color vision, and visual acuity. Photoreceptors undergo progressive degeneration over time in many hereditary and age-related retinal diseases. Despite the remarkable heterogeneity of disease-causing genes, environmental factors, and pathogenesis, the progressive death of rod and cone photoreceptors ultimately leads to loss of vision/blindness. There are currently no treatments available for retinal degeneration. Cyclic guanosine 3′, 5′-monophosphate (cGMP) plays a pivotal role in phototransduction. cGMP governs the cyclic nucleotide-gated (CNG) channels on the plasma membrane of the photoreceptor outer segments, thereby regulating membrane potential and signal transmission. By gating the CNG channels, cGMP regulates cellular Ca2+ homeostasis and signal transduction. As a second messenger, cGMP activates the cGMP-dependent protein kinase G (PKG), which regulates numerous targets/cellular events. The dysregulation of cGMP signaling is observed in varieties of photoreceptor/retinal degenerative diseases. Abnormally elevated cGMP signaling interferes with various cellular events, which ultimately leads to photoreceptor degeneration. In line with this, strategies to reduce cellular cGMP signaling result in photoreceptor protection in mouse models of retinal degeneration. The potential mechanisms underlying cGMP signaling-induced photoreceptor degeneration involve the activation of PKG and impaired Ca2+ homeostasis/Ca2+ overload, resulting from overactivation of the CNG channels, as well as the subsequent activation of the downstream cellular stress/death pathways. Thus, targeting the cellular cGMP/PKG signaling and the Ca2+-regulating pathways represents a significant strategy for photoreceptor protection in retinal degenerative diseases.

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