Batten disease is linked to altered expression of mitochondria-related metabolic molecules

Mitochondrial Dysfunction and Neurodegeneration in Lysosomal Storage Disorders

“…More recently, it was shown that mitochondrial cristae were reduced and disorganized in human iPSC-derived neurons for NCL induced by CLN3 mutations [43], were elongated in cerebellar precursor cells in a Cln3Δex7/8 knock-in mice [44], and showed no structural alterations (apart from some smaller mitochondria) in primary cultures from Cln3-/mouse neurons, in which oxygen consumption was nevertheless decreased [45]. Moreover, mitochondria were depolarized in a lymphoblast model of CLN3 NCL [46]. When considering fibroblasts from NCL patients carrying CLN1 and CLN6 mutations, mitochondria were fragmented and redistributed at the cell periphery, with increased expression levels of the voltage-dependent anion channel (VDAC) and complex IV, consistent with accumulation of mitochondria [47].…”

“…For instance, in patient derived NPC fibroblasts, ROS generation has been shown to be decreased [33], while for NCL human fibroblasts --associated with CLN2 and CLN3 [58] -and GD human fibroblasts [31], production of superoxide and hydrogen peroxide were found to be increased. In different studies using NCL human lymphoblasts [46], a yeast NPC model [32] or NPC human fibroblasts [69], a human oligodendryocyte cell line exposed to psychosine to model Krabbe disease [73], or mytoubes derived from a knockout mice model for Pompe disease [51], basal ROS and/or H 2 O 2 production were also increased. Of note, increased protein oxidation and lipid peroxidation, as well as DNA damage due to oxidative stress, were reported in the urine, plasma and leukocytes of MPS IV patients [68], in a yeast NPC model, in NPC human fibroblasts and in different NPC mice tissues [32,69,70], as well as in brain tissues of GM2 gangliosidosis mice [30] and in NCL patients [71].…”

Unbiased Cell-based Screening in a Neuronal Cell Model of Batten Disease Highlights an Interaction between Ca2+ Homeostasis, Autophagy, and CLN3 Protein Function

“…9C), suggesting the mitochondria in CbCln3 ⌬ex7/8/⌬ex7/8 cells cannot properly maintain their Ca 2ϩ levels, perhaps due to a reduced mitochondrial membrane potential. Mitochondrial membrane depolarization has been observed in CLN3 patient lymphoblasts (49). Finally, lysosomal Ca 2ϩ was measured by first depleting and clamping the other intracellular stores with ionomycin (2 M), then inducing lysosomal release by treatment with 200 M glycyl-L-phenylalanine-␤-naphthylamide (GPN) (25).…”

Secondary Cerebral Folate Deficiency Comorbidity in Neuronal Ceroid Lipofuscinosis

“…Damage of mitochondria in lysosomal disorders has also been reported. [6][7][8]10 In the absence of peripheral or nutritional folate deficiency, it is thought that decreased 5-MTHF may be secondary to a defect in the active ATP-dependent cerebral folate transport, increased consumption of folate in the CNS or related to dysfunction other pathways, for example, oxidative stress or respiratory chain dysfunction that may indirectly influence the folate pathway. 1,2,4 Van Beersel et al studied TPP1-deficient fibroblast and reported accentuated mitochondrial fragmentation thought to be due to the decrease in the quantity of regulatory proteins Mfn1 and Mfn2 and overexpression of BNIP3 (Bcl2/adenovirus E1B 19 kDa interacting protein 3), a proapoptotic BH3-only protein which is suggested to increase sensitivity of mitochondria to oxidative stress, mediating mitochondrial dysfunction inducing apoptosis, and neurodegeneration in LINCL.…”

“…1,2,4 Moreover, several studies also suggest that lysosomal dysfunction itself could affect mitochondrial function, leading to neuronal cell death. [6][7][8] Neuronal ceroid lipofuscinosis (NCL) is a degenerative disorder of the gray matter that is associated with progressive symptoms such as seizures, dementia, visual loss, and cerebral atrophy. NCL is often classified based on the age of onset and the clinical symptoms.…”