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Miranda AM, Herman M, Cheng R, Nahmani E, Barrett G, Micevska E, Fontaine G, Potier MC, Head E, Schmitt FA, Lott IT, Jiménez-Velázquez IZ, Antonarakis SE, Di Paolo G, Lee JH, Hussaini SA, Marquer C. Excess Synaptojanin 1 Contributes to Place Cell Dysfunction and Memory Deficits in the Aging Hippocampus in Three Types of Alzheimer's Disease. Cell Rep. 2018 Jun 5;23(10):2967-2975. PubMed.
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The University of Minnesota
This paper identified synaptojanin (synj1) variants associated with age of onset in both early and late-onset FAD cohorts. They also linked excess synj1 protein levels to synaptic loss and dysfunction in postmortem DS brains, as well as to hippocampus-based memory deficits in a mouse model overexpressing murine synj1.
These findings are very interesting. We have previously shown that increased synj1 expression contributes to ApoE4-associated cognitive deficits. The observations by Marquer and colleagues, in combination with ours (Zhu et al., 2015; Zhu et al., 2013) and others (McIntire et al., 2012) suggest that synaptojanin could be a good therapeutic target for treating cognitive impairment in AD.
For future studies, I would be interested in knowing how these synj1 SNPs affect synj1 function leading to AD-related pathology. Are they manifested as gain-of-toxic effects, which are different from synj1 variants with loss-of-function effects identified in PD patients?
I am also very intrigued by the results showing inverse correlation between synj1 protein expression and synaptic integrity in DS human brains. It would be interesting to see if similar patterns can be observed in postmortem AD brain tissue, and if ApoE4 worsens these changes based on our prior observations. Our previous data suggest that elevated synj1 expression in ApoE4 carriers was most prominent in early AD stages. It is possible that elevated synj1 expression with associated neuronal hyper-excitability is manifested as an early AD phenomenon which plays an important role in disease pathogenesis and development.
References:
Zhu L, Zhong M, Elder GA, Sano M, Holtzman DM, Gandy S, Cardozo C, Haroutunian V, Robakis NK, Cai D. Phospholipid dysregulation contributes to ApoE4-associated cognitive deficits in Alzheimer's disease pathogenesis. Proc Natl Acad Sci U S A. 2015 Sep 22;112(38):11965-70. Epub 2015 Sep 8 PubMed.
Zhu L, Zhong M, Zhao J, Rhee H, Caesar I, Knight EM, Volpicelli-Daley L, Bustos V, Netzer W, Liu L, Lucast L, Ehrlich ME, Robakis NK, Gandy SE, Cai D. Reduction of synaptojanin 1 accelerates Aβ clearance and attenuates cognitive deterioration in an Alzheimer mouse model. J Biol Chem. 2013 Nov 1;288(44):32050-63. PubMed.
McIntire LB, Berman DE, Myaeng J, Staniszewski A, Arancio O, Di Paolo G, Kim TW. Reduction of synaptojanin 1 ameliorates synaptic and behavioral impairments in a mouse model of Alzheimer's disease. J Neurosci. 2012 Oct 31;32(44):15271-6. PubMed.
View all comments by Dongming CaiTel Aviv University
This study adds new evidence to the concept that dysregulation of endocytic recycling of synaptic vesicles in neurons is an important biological pathway in the etiology of disorders associated with neuronal hyper-excitability. The authors found that synj1 polymorphisms are associated with familial and sporadic Alzheimer’s disease. In animal studies, the authors show that AD-associated synj1 overexpression causes an increase in the firing rate of CA1 principal cells, destabilization and enlargement of place fields, and hippocampus-dependent cognitive impairments. These results point to a causal link between increased synj1 levels and impairments in functioning of CA1 excitatory neurons.
Interestingly, autosomal-recessive inherited synj1 variants, leading to the loss of synj1 phosphatase function, recently have been shown to cause early onset pharmaco-resistant seizures and progressive neurological decline (Hardies et al., 2016). Moreover, mouse knockout studies have shown that loss-of-function variants in endophilin and amphiphysin, two synj1 binding proteins, also lead to severe epilepsy (Di Paolo et al., 2002; Milosevic et al., 2011). Thus, the fact that reduction in synj1 levels causes epilepsy should be taken into account when developing AD therapeutic strategies based on synj1-mediated inhibition of synaptic vesicle endocytosis pathway. Increased understanding of the bell-shaped relationship between synj1 expression and neuronal activity, at the single-neuron and network levels, will guide future development of novel treatments for AD and epilepsy patients.
References:
Hardies K, Cai Y, Jardel C, Jansen AC, Cao M, May P, Djémié T, Hachon Le Camus C, Keymolen K, Deconinck T, Bhambhani V, Long C, Sajan SA, Helbig KL, AR working group of the EuroEPINOMICS RES Consortium, Suls A, Balling R, Helbig I, De Jonghe P, Depienne C, De Camilli P, Weckhuysen S. Loss of SYNJ1 dual phosphatase activity leads to early onset refractory seizures and progressive neurological decline. Brain. 2016 Sep;139(Pt 9):2420-30. Epub 2016 Jul 19 PubMed.
Di Paolo G, Sankaranarayanan S, Wenk MR, Daniell L, Perucco E, Caldarone BJ, Flavell R, Picciotto MR, Ryan TA, Cremona O, De Camilli P. Decreased synaptic vesicle recycling efficiency and cognitive deficits in amphiphysin 1 knockout mice. Neuron. 2002 Feb 28;33(5):789-804. PubMed.
Milosevic I, Giovedi S, Lou X, Raimondi A, Collesi C, Shen H, Paradise S, O'Toole E, Ferguson S, Cremona O, De Camilli P. Recruitment of endophilin to clathrin-coated pit necks is required for efficient vesicle uncoating after fission. Neuron. 2011 Nov 17;72(4):587-601. PubMed.
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