Parkinson's disease-associated human P5B-ATPase ATP13A2 increases spermidine uptake

Abstract

P-type ion pumps are membrane transporters that have been classified into five subfamilies termed P1-P5. The ion transported by the P5-ATPases is not known. Five genes, ATP13A (ATPase type 13A) 1-ATP13A5, that belong to the P5-ATPase group have been identified in humans. Mutations of the human gene ATP13A2 underlie a form of PD (Parkinson's disease). Previous studies have suggested a relation between polyamines and P5B-ATPases. We have recently shown that the cytotoxicity induced by the polyamine analogue paraquat (1,1'-dimethyl-4,4'-bipyridinium), which is an environmental agent related to PD development, was increased in ATP13A2-expressing CHO (Chinese-hamster ovary) cells. In the present study we showed that ATP13A2-expressing CHO cells exhibit a 2-fold higher accumulation of spermidine. Increasing concentrations of spermidine reduced the viability of CHO cells stably expressing ATP13A2. The higher levels of spermidine attained by the ATP13A2-expressing CHO cells were correlated with an increase in the ATP-dependent spermidine uptake in an isolated subcellular fraction containing lysosomes and late endosomes. The results of the present study support the idea that the human P5B-ATPase ATP13A2 is involved in polyamine uptake.

Cellular function and pathological role of ATP13A2 and related P-type transport ATPases in Parkinson's disease and other neurological disorders

“…In mammalian CHO cells, ATP13A2 overexpression leads to a two-fold higher accumulation of the polyamine spermidine. It was shown that the ATP-dependent spermidine uptake was increased in a lysosomal and late endosomal fraction further supporting the notion that the ATP13A2 protein mediates polyamine uptake (De La Hera et al, 2013). The higher polyamine uptake rate might further explain the increased cytotoxic effects of paraquat, a toxic polyamine analogue that is an environmental risk factor for PD (Pinto Fde et al, 2012).…”

“…Along the same lines, loss of ATP13A2 and impaired mitochondrial clearance may explain the observed intolerance toward Mn 2+ (Gitler et al, 2009; Schmidt et al, 2009) and paraquat (Pinto Fde et al, 2012). Since polyamines can function as ROS scavengers, the increased uptake of polyamines (De La Hera et al, 2013) may protect ATP13A2 −/− cells toward oxidative stress, although high levels of polyamines are also toxic.…”

The Role of Glia in Stress

“…Using radioactive polyamines 59, 116, 117 and polyclonal antibodies specific for PUT 60 or SPM/SPD 23, 24, 25 , we and others have shown that PAs are taken up in brain 110, 122, and astrocytes are capable of taking up PAs. 60, 123–128 (Fig. 1B).…”

“…111, 167, 288 There are severe psychiatric disorders directly linked with neuroglia and PA dysfunction such as schizophrenia and mood disorders, where failure of PA exchange is seen 179–182 , autism with disorders in the PA and Na-H-exchange, 149, 289 depression which is associated with decreased glial cell mass, OCTs and PA levels, 173, 290 suicide which correlates with PA homeostatic imbalances, 291 aging where glial cells lose PAs 99, 100, 286 and downregulate Ca 2+ -signaling 236 and fear extinction where PAs reinforce extinction via NMDAR regulation. 292 Recently, many human CNS diseases have been linked with PA levels including Alzheimer’s disease 102, 293, 294 , Parkinson’s disease 128, 295, 296, 297 , Huntington’s disease 167, 298–301 and Amyotrophic lateral sclerosis. 186, 187, 302 In spite of a broad phenomenological description in the literature, there still remain functional links between PAs and glia in the brain that have not been mechanistically deciphered.…”

Parkinson's disease as a result of aging

“…This protective effect has not been shown for other sirtuins (Dillin & Kelly, 2007) which, as occurs with the sirtuin 2, may even promote the cell death in animal models of PD (Outeiro et al ., 2007). Other agents that could be useful for modulating both aging and PD are the insulin growth factors (Mattson et al ., 2004; de Cabo et al ., 2014; Numao et al ., 2014), spermidine (Pucciarelli et al ., 2012; De La Hera et al ., 2013), metformin (Patil et al ., 2014), and rapamycin (Malagelada et al ., 2010; Liu et al ., 2013). …”