PDZD8 Disruption Causes Cognitive Impairment in Humans, Mice, and Fruit Flies

Al-Amri, Ahmed; Armstrong, Paul; Amici, Mascia; Ligneul, Clémence; Rouse, James; El‐Asrag, Mohammed E.; Pantiru, Andreea; Vancollie, Valerie E.; Ng, Hannah; Ogbeta, Jennifer A; Goodchild, Kirstie; Ellegood, Jacob; Lelliott, Christopher J.; Mullins, Jonathan; Bretman, Amanda; Al‐Ali, Ruslan; Beetz, Christian; Alshamsi, Aisha; Lerch, Jason P.; Mellor, Jack R.; Sayegh, Abeer Al; Ali, Manir; Inglehearn, Chris F.; Clapcote, Steven J.

doi:10.1016/j.biopsych.2021.12.017

Cited by 15 publications

(10 citation statements)

References 77 publications

(175 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In contrast to the detrimental effects of increased tethering, reducing MERCs by knockdown of pdzd8 in Drosophila neurons dramatically delayed age-associated decline in locomotor activity and significantly extended median lifespan compared with control animals. Our results corroborate a recent study showing that adult Pdzd8 -deficient mice display increased locomotor activity compared with control littermates ( Al-Amri et al, 2022 ).…”

Section: Discussionsupporting

confidence: 92%

Decreasing pdzd8-mediated mito–ER contacts improves organismal fitness and mitigates Aβ₄₂toxicity

et al. 2022

View full text Add to dashboard Cite

Mitochondria-ER contact sites (MERCs) orchestrate many important cellular functions including regulating mitochondrial quality control through mitophagy and mediating mitochondrial calcium uptake. Here, we identify and functionally characterize the Drosophila ortholog of the recently identified mammalian MERC protein, Pdzd8. We find that reducing pdzd8-mediated MERCs in neurons slows age-associated decline in locomotor activity and increases lifespan in Drosophila. The protective effects of pdzd8 knockdown in neurons correlate with an increase in mitophagy, suggesting that increased mitochondrial turnover may support healthy aging of neurons. In contrast, increasing MERCs by expressing a constitutive, synthetic ER–mitochondria tether disrupts mitochondrial transport and synapse formation, accelerates age-related decline in locomotion, and reduces lifespan. Although depletion of pdzd8 prolongs the survival of flies fed with mitochondrial toxins, it is also sufficient to rescue locomotor defects of a fly model of Alzheimer’s disease expressing Amyloid β42 (Aβ42). Together, our results provide the first in vivo evidence that MERCs mediated by the tethering protein pdzd8 play a critical role in the regulation of mitochondrial quality control and neuronal homeostasis.

show abstract

Section: Discussionsupporting

confidence: 92%

Decreasing pdzd8-mediated mito–ER contacts improves organismal fitness and mitigates Aβ₄₂toxicity

et al. 2022

View full text Add to dashboard Cite

show abstract

“…The importance of the mitochondria-ER platform is particularly evident in neural cells. Astrocytic MERCSs facilitate vascular remodelling [21], and loss of PDZD8 (a molecular tethering protein that supports ERmitochondria contacts) disrupts neuronal cellular calcium dynamics [22] and synaptic plasticity [23]. In humans, recessive loss-of-function PDZD8 variants cause neurodevelopmental cognitive impairment [23].…”

Section: Mitochondrial Contact Sitesmentioning

confidence: 99%

Mitochondrial signalling and homeostasis: from cell biology to neurological disease

Collier¹,

Oláhová²,

McWilliams³

et al. 2023

Trends in Neurosciences

View full text Add to dashboard Cite

“…The direction of this correlation is also confirmed in the study, which showed the absence of irradiation effects on habituation against the background of anxiolytic therapy [ 82 ]. On the other hand, in both humans and animals, the disruption of habituation is strongly correlated with cognitive impairments [ 94 , 95 ] and vice versa [ 93 , 96 ]. Thus, both active OEB and rapid habituation of irradiated rodents indirectly indicate a possible enhancement of cognitive abilities.…”

Section: Mental Health and Ionizing Radiationmentioning

confidence: 99%

The Effects of Galactic Cosmic Rays on the Central Nervous System: From Negative to Unexpectedly Positive Effects That Astronauts May Encounter

Kokhan

Dobynde

2023

Biology

View full text Add to dashboard Cite

Galactic cosmic rays (GCR) pose a serious threat to astronauts’ health during deep space missions. The possible functional alterations of the central nervous system (CNS) under GCR exposure can be critical for mission success. Despite the obvious negative effects of ionizing radiation, a number of neutral or even positive effects of GCR irradiation on CNS functions were revealed in ground-based experiments with rodents and primates. This review is focused on the GCR exposure effects on emotional state and cognition, emphasizing positive effects and their potential mechanisms. We integrate these data with GCR effects on adult neurogenesis and pathological protein aggregation, forming a complete picture. We conclude that GCR exposure causes multidirectional effects on cognition, which may be associated with emotional state alterations. However, the irradiation in space-related doses either has no effect or has performance enhancing effects in solving high-level cognition tasks and tasks with a high level of motivation. We suppose the model of neurotransmission changes after irradiation, although the molecular mechanisms of this phenomenon are not fully understood.

show abstract

PDZD8 Disruption Causes Cognitive Impairment in Humans, Mice, and Fruit Flies

Cited by 15 publications

References 77 publications

Decreasing pdzd8-mediated mito–ER contacts improves organismal fitness and mitigates Aβ₄₂toxicity

Decreasing pdzd8-mediated mito–ER contacts improves organismal fitness and mitigates Aβ₄₂toxicity

Mitochondrial signalling and homeostasis: from cell biology to neurological disease

The Effects of Galactic Cosmic Rays on the Central Nervous System: From Negative to Unexpectedly Positive Effects That Astronauts May Encounter

Contact Info

Product

Resources

About

PDZD8 Disruption Causes Cognitive Impairment in Humans, Mice, and Fruit Flies

Cited by 15 publications

References 77 publications

Decreasing pdzd8-mediated mito–ER contacts improves organismal fitness and mitigates Aβ42toxicity

Decreasing pdzd8-mediated mito–ER contacts improves organismal fitness and mitigates Aβ42toxicity

Mitochondrial signalling and homeostasis: from cell biology to neurological disease

The Effects of Galactic Cosmic Rays on the Central Nervous System: From Negative to Unexpectedly Positive Effects That Astronauts May Encounter

Contact Info

Product

Resources

About

Decreasing pdzd8-mediated mito–ER contacts improves organismal fitness and mitigates Aβ₄₂toxicity

Decreasing pdzd8-mediated mito–ER contacts improves organismal fitness and mitigates Aβ₄₂toxicity