Accumulation of sphingolipid activator proteins (SAPs) A and D in granular osmiophilic deposits in miniature Schnauzer dogs with ceroid‐lipofuscinosis

Abstract

The neuronal ceroid-lipofuscinoses (NCL, Batten disease) are fatal inherited neurodegenerative diseases of children characterized by retinal and brain atrophy and the accumulation of electron-dense storage bodies in cells. Mutations in different genes underlie different major forms. The infantile disease (CLN-1, McKusick 256730) is distinguished by the storage of the sphingolipid activator proteins (SAPs) A and D in distinctive granular osmiophilic deposits (GRODs). This contrasts with the other major forms, where subunit c of mitochondrial ATP synthase is stored in various multilamellar profiles. Ceroid-lipofuscinoses also occur in dogs, including a form in miniature Schnauzers with distinctive granular osmiophilic deposit-like storage bodies. Antisera to SAPs A and D reacted to these storage bodies in situ. The presence of SAP D was confirmed by Western blotting and of SAP A by protein sequencing. Neither subunit c of mitochondrial ATP synthase nor of vacuolar ATPase is stored. This suggests that there are two families of ceroid-lipofuscinoses, the subunit c-storing forms, and those in which SAPs A and D, and perhaps other proteins, accumulate. Further work is required to determine whether other forms with granular osmiophilic deposits belong to the latter class and the genetic relationships between them and the human infantile disease.

Neuronal ceroid lipofuscinosis: clinical and morphologic findings in nine affected Polish Owczarek Nizinny (PON) dogs

“…Both PON dogs and Miniature Schnauzers lack pronounced brain atrophy as well as SCMAS storage; behavioral changes and blindness associated with retinal degeneration occur in both breeds 1,17 . Furthermore, SAP A and D storage is present in PON dogs as well as in Miniature Schnauzers 4 . This pattern of neuronal storage is unusual in canine and human forms of NCL: in most of the known NCL variants, SCMAS is the predominant storage protein 18 …”

“…Accumulation of subunit c of mitochondrial adenosine triphosphate (ATP) synthase (SCMAS) has been demonstrated as the dominant storage protein in the late infantile and juvenile human forms of NCL, as well as in sheep, cattle and several dog breeds 2 . In contrast, the sphingolipid activator proteins (SAPs or saposins) A and D are the major protein components of storage bodies in human infantile disease and in the affected Miniature Schnauzer dog 3,4 …”

Canine neuronal ceroid lipofuscinoses: Promising models for preclinical testing of therapeutic interventions

“…For some of these breeds including Corgi, Spitz, and Yugoslavian Shepherd only limited clinical descriptions have been published (Bichsel and Vandevelde, 1982; Jolly et al, 1994b; Pickett et al, 1992). Histopathological confirmation of NCL-like storage body accumulation has been presented for Dalmatians (Goebel, 1992; Goebel and Dahme, 1985; Goebel and Dahme, 1986), a single Labrador Retriever (Rossmeisl et al, 2003), two related Miniature Schnauzers (Palmer et al, 1997b; Smith et al, 1996), a number of apparently unrelated Cocker Spaniels (Jolly et al, 1994a; Minatel et al, 2000; Nimmo Wilkie and Hudson, 1982), three Australian Shepherd littermates (Katz et al, 2008), a Standard Poodle (Cantile et al, 1996), two related Saluki dogs (Appleby et al, 1982), two Longhaired Dachshunds (Vandevelde and Fatzer, 1980), a Wirehaired Dachshund (Cummings and de Lahunta, 1977), a mixed-breed dog with terrier ancestry (Hoover et al, 1984), and at least 9 PON dogs, many of which were not closely related (Narfstrom and Wrigstad, 1995; Narfström et al, 2007; Wrigstad et al, 1995). …”

“…These reports range from very limited descriptions of clinical signs in one or a few isolated cases (Appleby et al, 1982; Bichsel and Vandevelde, 1982; Cantile et al, 1996; Cummings and de Lahunta, 1977; Hoover et al, 1984; Jolly et al, 1994b; Pickett et al, 1992; Rossmeisl et al, 2003; Vandevelde and Fatzer, 1980), to more thorough characterizations of the disease phenotypes, including histopathology, in multiple affected dogs of the same breed (Goebel, 1992; Goebel and Dahme, 1985; Goebel and Dahme, 1986; Jolly et al, 1994a; Jolly et al, 1997; Kirchhoff and Kobe, 1994; Minatel et al, 2000; Narfström et al, 2007; Nimmo Wilkie and Hudson, 1982; Palmer et al, 1997b; Smith et al, 1996). There is a wide range in the amount of evidence used to support putative diagnoses of NCL in these cases.…”

Juvenile Neuronal Ceroid-Lipofuscinosis (Batten Disease): A Brief Review and Update

“…Histochemically, lysosomal acid phosphatase activity is associated with the storage material. Immunohistochemcially, a few extremely hydrophobic proteins are detected in the lipopigment storage material; these include subunit c of the mitochondrial ATP synthase, and sphingolipid activator proteins or saposins A and D [35,42,[48][49][50][51][52].…”