Lysosomal TPCN (two pore segment channel) inhibition ameliorates beta-amyloid pathology and mitigates memory impairment in Alzheimer disease

Tong, Benjamin Chun‐Kit; Wu, Aston Jiaxi; Huang, Alexis Shiying; Dong, Rui; Malampati, Sandeep; Iyaswamy, Ashok; Krishnamoorthi, Senthilkumar; Sreenivasmurthy, Sravan Gopalkrishnashetty; Zhu, Zhou; Su, Cheng-Fu; Liu, Jia; Song, Ju‐Xian; Lu, Jiahong; Tan, Jieqiong; Pan, Weidong; Li, Min; Cheung, King‐Ho

doi:10.1080/15548627.2021.1945220

Cited by 30 publications

(32 citation statements)

References 63 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Notably, mutations in presenilin 1 that cause familial forms of AD disrupt lysosome function and autophagy ( Cataldo et al, 2004 ; Coen et al, 2012 ; Lee et al, 2015 ; Lee et al, 2010 ; Neely et al, 2011 ; Tong et al, 2021 ), linking lysosomal impairments directly to AD. Lysosome acidification defects have also been linked to the characteristic axonal dystrophy of AD ( Fig.…”

Section: Axonostasis Failure In Neurodegenerative Diseasesmentioning

confidence: 99%

Neuronal endolysosomal transport and lysosomal functionality in maintaining axonostasis

Roney

Cheng

Sheng

2022

Journal of Cell Biology

View full text Add to dashboard Cite

Lysosomes serve as degradation hubs for the turnover of endocytic and autophagic cargos, which is essential for neuron function and survival. Deficits in lysosome function result in progressive neurodegeneration in most lysosomal storage disorders and contribute to the pathogenesis of aging-related neurodegenerative diseases. Given their size and highly polarized morphology, neurons face exceptional challenges in maintaining cellular homeostasis in regions far removed from the cell body where mature lysosomes are enriched. Neurons therefore require coordinated bidirectional intracellular transport to sustain efficient clearance capacity in distal axonal regions. Emerging lines of evidence have started to uncover mechanisms and signaling pathways regulating endolysosome transport and maturation to maintain axonal homeostasis, or “axonostasis,” that is relevant to a range of neurologic disorders. In this review, we discuss recent advances in how axonal endolysosomal trafficking, distribution, and lysosomal functionality support neuronal health and become disrupted in several neurodegenerative diseases.

show abstract

Section: Axonostasis Failure In Neurodegenerative Diseasesmentioning

confidence: 99%

Neuronal endolysosomal transport and lysosomal functionality in maintaining axonostasis

Roney

Cheng

Sheng

2022

Journal of Cell Biology

View full text Add to dashboard Cite

show abstract

“…Hence, both the role of PSEN1 in lysosomal acidification as well as the TRPML1 hyperactivity theory remain controversial. The studies by Tong et al [ 46 ] and Hockey et al [ 2 ] suggest hyperactivity of TPC2 and/or a beneficial effect of TPC2 inhibition that underscores the relevance of TPC2 in neurodegenerative disease conditions, but in these studies, it remains to be clarified what causes TPC2 hyperactivity, for example, excess NAADP. Direct channel activity measurements would be helpful in these models.…”

Section: Discussionmentioning

confidence: 99%

“…A recent work by Tong et al (2022) [ 46 ] claimed that exaggeration of TPC2 activity in SH-SY5Y neuroblastoma cells expressing mutant Presenilin 1 (PSEN1) and human fibroblasts from familial Alzheimer’s disease patients results in the reduction of lysosomal Ca 2+ , which in turn accelerates the Ca 2+ /H + exchanger to expel H + leading to lysosomal alkalinization and reduction in autophagy clearance of amyloids. Vice versa, inhibition of TPC2 by tetrandrine or Ned-19 or via siRNA treatment reportedly restored lysosomal Ca 2+ and pH and rescued autophagy [ 46 ]. Albeit potentially different from the LSD models we investigated, the claim is that in AD patient fibroblasts and PSEN1 mutant neuroblastoma cells, blocking TPC2 would be beneficial compared to activation.…”

Section: Is It All Clear Then?mentioning

confidence: 99%

“…The main difference between the groups is the timing of pulse and chase and the different biological models used. Tong et al [ 46 ] used a human neuroblastoma cell line and fAD fibroblasts while the Nixon group [ 52 , 53 ] and Coen et al [ 57 ] used mouse cell lines, neurons isolated from PSEN1 KO mouse embryos and MEF, respectively. Due to the wide pH range present in endocytic organelles, addressing endolysosomal pH is a challenging task, especially when using endocytic tracers combined with pH sensitive dyes [ 58 ].…”

Section: Is It All Clear Then?mentioning

confidence: 99%

See 1 more Smart Citation

Neurodegenerative Lysosomal Storage Disorders: TPC2 Comes to the Rescue!

Castro

Kudrina

Jaślan

et al. 2022

Cells

View full text Add to dashboard Cite

Lysosomal storage diseases (LSDs) resulting from inherited gene mutations constitute a family of disorders that disturb lysosomal degradative function leading to abnormal storage of macromolecular substrates. In most LSDs, central nervous system (CNS) involvement is common and leads to the progressive appearance of neurodegeneration and early death. A growing amount of evidence suggests that ion channels in the endolysosomal system play a crucial role in the pathology of neurodegenerative LSDs. One of the main basic mechanisms through which the endolysosomal ion channels regulate the function of the endolysosomal system is Ca2+ release, which is thought to be essential for intracellular compartment fusion, fission, trafficking and lysosomal exocytosis. The intracellular TRPML (transient receptor potential mucolipin) and TPC (two-pore channel) ion channel families constitute the main essential Ca2+-permeable channels expressed on endolysosomal membranes, and they are considered potential drug targets for the prevention and treatment of LSDs. Although TRPML1 activation has shown rescue effects on LSD phenotypes, its activity is pH dependent, and it is blocked by sphingomyelin accumulation, which is characteristic of some LSDs. In contrast, TPC2 activation is pH-independent and not blocked by sphingomyelin, potentially representing an advantage over TRPML1. Here, we discuss the rescue of cellular phenotypes associated with LSDs such as cholesterol and lactosylceramide (LacCer) accumulation or ultrastructural changes seen by electron microscopy, mediated by the small molecule agonist of TPC2, TPC2-A1-P, which promotes lysosomal exocytosis and autophagy. In summary, new data suggest that TPC2 is a promising target for the treatment of different types of LSDs such as MLIV, NPC1, and Batten disease, both in vitro and in vivo.

show abstract

“…The relationship between Aβ and autophagy is complicated. First, Aβ is degraded through autophagy, and several studies show a decreased Aβ level in cells and improved cognitive ability in an AD mouse model when autophagy is induced [ 244 , 245 , 246 , 247 ]. Second, Aβ may also be generated inside autophagosomes because both APP (amyloid beta precursor protein) and PSEN1, an enzyme involved in the cleavage of APP to form Aβ, are found within the autophagosome [ 235 ].…”

Section: Autophagy and Neurodegenerative Diseasesmentioning

confidence: 99%

The Emerging Roles of Autophagy in Human Diseases

Lei

Klionsky

2021

Biomedicines

View full text Add to dashboard Cite

Autophagy, a process of cellular self-digestion, delivers intracellular components including superfluous and dysfunctional proteins and organelles to the lysosome for degradation and recycling and is important to maintain cellular homeostasis. In recent decades, autophagy has been found to help fight against a variety of human diseases, but, at the same time, autophagy can also promote the procession of certain pathologies, which makes the connection between autophagy and diseases complex but interesting. In this review, we summarize the advances in understanding the roles of autophagy in human diseases and the therapeutic methods targeting autophagy and discuss some of the remaining questions in this field, focusing on cancer, neurodegenerative diseases, infectious diseases and metabolic disorders.

show abstract

Lysosomal TPCN (two pore segment channel) inhibition ameliorates beta-amyloid pathology and mitigates memory impairment in Alzheimer disease

Cited by 30 publications

References 63 publications

Neuronal endolysosomal transport and lysosomal functionality in maintaining axonostasis

Neuronal endolysosomal transport and lysosomal functionality in maintaining axonostasis

Neurodegenerative Lysosomal Storage Disorders: TPC2 Comes to the Rescue!

The Emerging Roles of Autophagy in Human Diseases

Contact Info

Product

Resources

About