TMEM230 Accumulation in Granulovacuolar Degeneration Bodies and Dystrophic Neurites of Alzheimer’s Disease

Abstract

Transmembrane Protein 230 (TMEM230) is a newly identified protein associated with Parkinson's disease (PD) found in Lewy bodies and Lewy neurites of patients with PD or dementia with Lewy body disease. However, TMEM230 has not yet been investigated in the most common neurodegenerative disorder, Alzheimer's disease (AD). Here, we demonstrate that the expression of TMEM230 is specifically increased in neurons in AD patients. Importantly, both granulovacuolar degeneration (GVD) and dystrophic neurites (DNs), two prominent characteristic pathological structures associated with AD, contain TMEM230 aggregates. TMEM230 immunoreactivity can be detected in neurofibrillary tangles-containing neurons and hyperphosphorylated tau positive DNs. TMEM230 accumulation is also noted around senile plaques. These findings identifying TMEM230 as a component of GVD and DNs suggest TMEM230 dysregulation as a likely mechanism playing an important role in the pathogenesis of AD.

Dense core vesicle markers in CSF and cortical tissues of patients with Alzheimer’s disease

“…Therefore, our results involve the regulated secretory pathway in AD-related GVD. This is supported by reports showing the presence of the SV protein TMEM230, the Golgi apparatus Golgin A4, and components of the endoplasmic reticulum unfolded protein response in GVD bodies [ 56 , 61 – 63 ]. Because in addition to the hippocampus, the parietal cortex can also display GVD [ 58 ], our results of elevated levels of the precursor form of PC2 in AD homogenates point to non-processed PC2 as the main form in GVD bodies, which may be related to the high tendency of proPC2 to form large aggregates [ 64 ].…”

Untangling the origin and function of granulovacuolar degeneration bodies in neurodegenerative proteinopathies

“…This indicates a specific association between GVBs and early tau pathology. However, occasionally GVBs are also observed in cells that appear to be free of tau pathology in the human tauopathy [ 5 , 43 , 68 , 90 , 99 , 100 , 119 , 122 , 125 , 135 ] and tau Tg mouse [ 66 , 67 ] brain. Most quantifications range between ~ 2% and ~ 25% of GVB-bearing cells without immunodetection of tau pathology [ 5 , 66 , 67 , 90 , 122 , 135 ].…”

“…This suggest that selective targeting or degradation mechanisms are at play in GVBs. Furthermore, a plethora of other proteins involved in various cellular processes have been found in GVBs (for a tabular overview of GVB-localizing proteins discovered till 2016 see [ 65 ]; in our literature search, we additionally came across publications reporting GVB localization in tissue for PKR [ 135 ], phosphorylated p300 [ 5 ], PICALM [ 2 ], annexin2 [ 95 ], LRRK2 [ 95 ] and reticulon-3 [ 36 ] and publications after 2016 showed the GVB localization of TMEM230 [ 119 ], Dvl3 [ 93 ], rapsyn [ 93 ], APC [ 93 ], PrP [ 142 ], Golgin A4 [ 69 ], phosphorylated (S65) ubiquitin [ 45 ], SSBP1 [ 45 ], nucleolin [ 38 ], SIL1 [ 73 ], NF-κB [ 145 ], GM130 [ 148 ], β-COP [ 148 ], matrin-3 [ 148 ], G3BP [ 148 ] and immunoreactivity of GVBs for an anti-sialic acid antibody [ 94 ] (for phospho-specific antibodies see Table 3 )). In conclusion, regardless of the presence of proteolytic activity markers, the GVB core harbors a variety of proteins, including various markers of cellular stress and potentially harmful proteins.…”

Interaction between TRPML1 and p62 in Regulating Autophagosome-Lysosome Fusion and Impeding Neuroaxonal Dystrophy in Alzheimer’s Disease

“…Alzheimer's disease (AD), the commonest cause of dementia, is still considered as one of the greatest challenges in public health of the 21 st century [ 1 ]. AD is characterized by the presence of two key hallmark findings in pathology: neurofibrillary tangles and senile plaques, along with other dominant pathological changes such as neuronal loss and dystrophic neurites [ 2 ]. During the natural cause of ageing, selective intraneuronal amyloid- β (A β ) accumulation and oligomerization in adult life may potentially lead to the degeneration of basal forebrain cholinergic neurons in AD [ 3 ].…”