Mechanistic and therapeutic role of Drp1 in the pathogenesis of Alzheimer's disease

Bera, Arpita; Lavanya, Gantyada; Reshmi, Ravada; Dev, Kapil; Kumar, Rahul

doi:10.1111/ejn.15611

Cited by 20 publications

(9 citation statements)

References 201 publications

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“…In agreement, several groups have reported the potential of the pro-myelinating agent clemastine in reducing CNS amyloid pathologies and ameliorating cognitive deficits in AD mouse models [63][64][65]. Regarding the Drp1 hyperactivation provoking mitochondrial dysfunctions of OLs in AD [59], it is presumably not a cause but rather a consequence of amyloid-beta accumulation in these cells [66,67]. Zhang et al have shown that Drp1 is aberrantly hyperactivated in mature OLs cultured with cell-internalizable amyloidbeta [59,68].…”

Section: Exercise Counteracts Aging Brain Demyelinationmentioning

confidence: 70%

Physical Exercise Counteracts Aging-Associated White Matter Demyelination Causing Cognitive Decline

Butt,

Tobiume,

et al. 2024

Aging and disease

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In the central nervous system, oligodendrocytes wrap around neuronal axons to form myelin, an insulating layer or sheath that allows for the efficient conductance of action potentials. In addition to structural insulation, myelin provides encased axons with nutrient, metabolic and defensive support. Demyelination, or myelin loss, can therefore cause axonal dysfunction, leading to neurological impairment and disease. In Alzheimer's disease (AD), progressive white matter demyelination is acknowledged as one of the earliest pathologies preceding symptom onset. Unfortunately, current pharmacotherapy for slowing demyelination or promoting remyelination in AD is nonexistent. Exercise is recognized for its wide-ranging benefits to human health, including improved mental health and the prevention of lifestyle-related diseases. Mounting evidence suggests the contribution of physical activity in delaying the progression of dementia in elderly populations. Recent mechanistic studies have shown that exercise facilitates myelination in the brain through the vitalization of intrinsic pro-myelination cues, such as increased neurotrophic factors and electrical activity. In this review, we summarize and discuss the potential of physical exercise on counteracting aging-associated white matter demyelination, which causes cognitive decline in AD. We highlight the need of further basic and clinical research investigations on this topic to establish novel approaches for healthy and improved brain aging.

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Section: Exercise Counteracts Aging Brain Demyelinationmentioning

confidence: 70%

Physical Exercise Counteracts Aging-Associated White Matter Demyelination Causing Cognitive Decline

Butt,

Tobiume,

et al. 2024

Aging and disease

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“…From a clinical point of view, a SNP within the miR-1229 gene, which is expected to increase miR-1229-3p expression, was recently associated with increased risk for Alzheimer’s disease ( 45 ). Since both mitochondrial fragmentation and mitophagy deficiencies have been implicated in Alzheimer’s disease and several other neurodegenerative disorders ( 38, 46 ), investigating the role of the miR-1229-3p-Pink1 interaction in such disorders might be a promising direction for future research.…”

Section: Discussionmentioning

confidence: 99%

A human-specific microRNA controls the timing of excitatory synaptogenesis

Soutschek,

Bianco,

Galkin

et al. 2023

Preprint

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Neural circuit development in the human cortex is considerably prolonged in comparison to non-human primates, a trait that contributes to the remarkable cognitive capacity of modern humans. Here, we explore the regulatory role of non-coding RNAs, which dramatically expanded during brain evolution, in synapse development of human-induced pluripotent stem-cell derived neurons. Inhibition of a human-specific microRNA, miR-1229-3p, results in accelerated formation of excitatory synapses and enhanced synaptic transmission. Mechanistically, miR-1229-3p controls mitochondrial homeostasis by targeting important regulators of mitochondrial autophagy and fission, such as Pink1. Stimulation of mitochondrial metabolism rescues decreased calcium buffering in miR-1229-3p depleted neurons. Our findings reveal an important function of human-specific miR-1229-3p in developmental timing of human synaptogenesis and generally implicate non-coding RNAs in the control of human connectivity and cognition.One-Sentence SummaryA human-specific microRNA slows down the formation and maturation of neuronal synapses by reducing mitochondrial metabolism and renewal.

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“…Several research studies are focusing on Drp1 PTMs in fission. According to recent findings, Drp1 controls the dynamics of the fission process by moving from the cytosol to the OMM, where it interacts with other proteins that are part of the fission machinery, such as Fis1, Mff, Mid49, and Mid51 [ 27 , 28 ]. Table 1 presents critical information about the locations and molecular functions of major mitochondrial fission proteins.…”

Section: Mitochondrial Fissionmentioning

confidence: 99%

The Drp1-Mediated Mitochondrial Fission Protein Interactome as an Emerging Core Player in Mitochondrial Dynamics and Cardiovascular Disease Therapy

Zerihun

Sukumaran

Qvit

2023

IJMS

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Mitochondria, the membrane-bound cell organelles that supply most of the energy needed for cell function, are highly regulated, dynamic organelles bearing the ability to alter both form and functionality rapidly to maintain normal physiological events and challenge stress to the cell. This amazingly vibrant movement and distribution of mitochondria within cells is controlled by the highly coordinated interplay between mitochondrial dynamic processes and fission and fusion events, as well as mitochondrial quality-control processes, mainly mitochondrial autophagy (also known as mitophagy). Fusion connects and unites neighboring depolarized mitochondria to derive a healthy and distinct mitochondrion. In contrast, fission segregates damaged mitochondria from intact and healthy counterparts and is followed by selective clearance of the damaged mitochondria via mitochondrial specific autophagy, i.e., mitophagy. Hence, the mitochondrial processes encompass all coordinated events of fusion, fission, mitophagy, and biogenesis for sustaining mitochondrial homeostasis. Accumulated evidence strongly suggests that mitochondrial impairment has already emerged as a core player in the pathogenesis, progression, and development of various human diseases, including cardiovascular ailments, the leading causes of death globally, which take an estimated 17.9 million lives each year. The crucial factor governing the fission process is the recruitment of dynamin-related protein 1 (Drp1), a GTPase that regulates mitochondrial fission, from the cytosol to the outer mitochondrial membrane in a guanosine triphosphate (GTP)-dependent manner, where it is oligomerized and self-assembles into spiral structures. In this review, we first aim to describe the structural elements, functionality, and regulatory mechanisms of the key mitochondrial fission protein, Drp1, and other mitochondrial fission adaptor proteins, including mitochondrial fission 1 (Fis1), mitochondrial fission factor (Mff), mitochondrial dynamics 49 (Mid49), and mitochondrial dynamics 51 (Mid51). The core area of the review focuses on the recent advances in understanding the role of the Drp1-mediated mitochondrial fission adaptor protein interactome to unravel the missing links of mitochondrial fission events. Lastly, we discuss the promising mitochondria-targeted therapeutic approaches that involve fission, as well as current evidence on Drp1-mediated fission protein interactions and their critical roles in the pathogeneses of cardiovascular diseases (CVDs).

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Mechanistic and therapeutic role of Drp1 in the pathogenesis of Alzheimer's disease

Cited by 20 publications

References 201 publications

Physical Exercise Counteracts Aging-Associated White Matter Demyelination Causing Cognitive Decline

Physical Exercise Counteracts Aging-Associated White Matter Demyelination Causing Cognitive Decline

A human-specific microRNA controls the timing of excitatory synaptogenesis

The Drp1-Mediated Mitochondrial Fission Protein Interactome as an Emerging Core Player in Mitochondrial Dynamics and Cardiovascular Disease Therapy

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