Synapse / Neuronal pentraxins / TDP43 / TMEM106B / TMEM175

Functional

	Pre-synapse	animal	human	Post-synapse	animal	human
Voltage or calcium fluctuations
Neurotransmitter release & vesicle recycling (transmembrane protein)
Synchronous calcium activity

Functional vs Structural: functional synapse changes often coincide with structural adaptations

• synaptic connectivity: the overall synaptic strength of the neuronal network – rather than the strength of a single synapse

Neuronal pentraxins

• Function
  • Involved in activity-dependent synaptic plasticity [1, 11, 32].
• 종류

	NPTX1	NPTX2 (Neuronal pentraxin II)	neuronal pentraxin receptor (NPTXR).
synonym		(= NARP (neuronal activity-regulated pentraxin),
function		it induces the formation of new excitatory synapses and the regulation of alphaamino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptor clustering at established synapses [7, 22, 23].

Synaptic change in PD

(Moran, 2008 #1102)	sPD	postmortem	NPTX2) is the most highly upregulated gene in the Parkinsonian substantia nigra based on IHC, our whole genome expression (microarray가 이것?), Novel component of LB & LN (co localized with aSyn)	NPTX2 is also known as the neuronal activity-regulated protein (Narp), which is secreted and involved in long-term neuronal plasticity. Narp further regulates AMPA receptors which have been found to mediate highly selective non-apoptotic cell death of dopaminergic neurons
(Wilson, 2020 #902)	sPD	Imaging	(A)

Target Identification

Cerevance

NETSseq is Rev

TDP43

(Zhao, 2015 #2008)

Wild-type, truncated 25 kD Cterminal fragments, or mutant forms of TDP-43 all activated microglia and upregulated NOX2, TNF-α, and IL-1β, with WT forms being significantly less effective in activating microglia. This response to TDP-43 was mediated by its interaction with the microglial surface CD14 receptor and subsequent stimulation of the NF-κB and AP-1 pathways, as well as the intracellular inflammasome. At the cell surface, CD14 blocking antibodies suppressed microglial NF-κB activation and proinflammatory cytokine production mediated by TDP-43. Intracellularly, the NLRP3 inflammasome was induced and functional caspase-1 was produced augmenting the release of mature IL-1β.

(Deora, 2020 #2009)

TDP-43 wild-type and mutant proteins could also activate microglial inflammasomes in a NLRP3-dependent manner.

TMEM106B

• TMEM106B is cleaved off from membrane by proteases, so I guess PROTAK approach might be interesting.
• TMEM106B builds amyloid like fibrils in FTLD-TDP which might coexist with TDP-43 aggregates (maybe non-fibrillar morphology).
• Variants
  • There is protective allele rs3173615 which causes TMEM106B p.T185S, the coding variant mutation. It seems it interacts with PRGN mutations.
  • J. Neurochem. (2013) 126, 781—791 This paper shows that S185 degrades faster than T185 TMEM106B, potentially due to differences in N-glycosylation at residue N183.
• Arthur:
  • My view is that TMEM106b is definitely a potential target that we should be thinking about and working on but I think that further validation is needed in terms of its role in disease progression.
  • TMEM175 is a lysosomal potassium channel that plays a role in maintaining lysosomal functioning, presumably by maintaining the transmembrane potential and pH across the lysosomal membrane. TMEM175 resides on chromosome 4 and is under a highly significant peak of association with Parkinson’s disease. Although there was initially some question regarding the specific genes responsible (e.g. DGKQ is also in this genomic region), more recent work has built a strong case that TMEM175 is responsible for the association. Jinn et al. 2017 (https://www.pnas.org/content/114/9/2389) showed that TMEM175 deficiency decreases lysosomal and GCase activity, impairs autophagy, and impacts on mitochondrial function, and increases susceptibility to exogenous α-syn fibrils.
  • Therefore, activators of TMEM175 may improve lysosomal function and autophagy.
  • The finding that a fragment of TMEM106b forms amyloid structures in multiple neurodegenerative disorders is very interesting but we need to figure out whether it plays a causative role with regard to disease progression or whether it is just prone to cleavage and aggregation in neurodegenerative disorders.
  • I have at least two reasons for skepticism:
  • In the paper by Chang et al. they find TMEM1006b fragments constitute amyloid fibrils in FTLD-TDP, PSP and DLB. The brain distribution and cellular pathology seen in these disorders are different. This makes it seem unlikely that TMEM106b fragments are primarily responsible for the pathology.
  • As I mentioned in an earlier email, TMEM106b cannot be the whole story. For example, in FTLD-TDP we know that TDP43 mislocalization is pathogenic, and it would therefore seem unlikely that clearing TMEM106b fragments would ameliorate disease.
  • I do certainly believe that the recent papers are interesting. I do think that there could be an interaction effect between TMEM106b fragments and TDP43 and Tau.
  • Can we develop a tool molecule, perhaps an antibody or an inhibitor of cleavage to study these questions in relevant cellular and animal models before heading down the very long road to developing a molecular glue?

TMEM175 (Transmembrane Protein 175)

Good review: (Wu, 2023 #2641)

• xlviii) In chr 4p16.3
• xlix) = TMEM175/GAK/DGKQ locus, (DGKQ is also in this genomic region)
• l) Function: (Chang et al. 2017, PMID 28892059) encode a potassium channel that can regulate lysosomal function32,
• li) TMEM175 forms a voltage-independent and non-inactivating K+ channel in endosomes and lysosomes a. Inward cation current (negative) denotes the movement of positive charges out of the organelle lumen into cytosol (bath) b.

ression

c. TMEM175 is highly expressed in oligodendrocyte progenitor cells (chia 2021 2nd)

	Variants	Epidemiology for PD	impact
(Krohn et al. 2020, PMID 31658403)	p.M393T (rs34311866) T>C	(Krohn et al. 2020, PMID 31658403) 1.37 (약 0.2 vs 0.3), (Chang, 2017 #1182) 1.20-1.27 (0.212 vs 0.184) -dbSNP: T=0.73645, C=0.26355 -Comp Bio (다 PD겠지?): hetero 0.35, homo 0.06 OR이 대체로 적네!	TMEM175 p.M393T creates a polar side-chain in the hydrophobic core of the transmembrane, which could destabilize the domain and thus impair either its assembly, maturation, or trafficking.
	p.Q65P (Rs34884217) A>C	0.72 (frequency 0.0931)	p.Q65P variant may increase stability and ion conductance of the transmembrane protein ('protective variant')

mary

etics	M393T	M393T → Association with PD development
	M393T	M393T → Association with PD progression ( ↓ AAO, average reduction of 0.6 years (Blauwendraat, 2019 #794) ), Iwaki 2019에서도 ↓ AAO 증명함.

Uncertain Spans

location	text/status	reason
Top Functional table	column count	Pre-synapse / animal / human / Post-synapse / animal / human columns are visible but every data cell in this crop is empty.
(Wilson, 2020 #902) Imaging	bar graph cell content	Bar graph and brain-region category labels are visible but not transcribed as text values; values listed in format_notes.
Cerevance row	NETSseq is Rev	Row is partly obscured by colored band overlays; only NETSseq is Rev is reliably readable.
TMEM106B Chang reference	TMEM1006b	Source spelling has an extra 0; preserved as written.
TMEM175 section title	ression (next to c. TMEM175 is highly expressed...)	Section heading is partly cut at the left edge; visible fragment is ression (likely Expression).